metabolic --＞ immune reprograming(만성염증 대사 재프로그래밍) 생화학적 이해!!

[문형철]

노화, 만성염증은

세포의 영양소(nutrient) sensing에 문제가 발생한 것

metabolic reprogramming을 통해 면역세포의 기능을 정상화할 수 있음.

metabolic reprogramming(면역세포 기능 정상화)는 어떻게 가능한가?

문치연 핵심 정리 중

1) ortho-molecular medicine의 관점 : 비타민 d 고농도, 타우린, probiotics .... anti-oxidant(비타민 C), 활성산소 덜 만들며 기능잘하게 하기(비타민 B -모든 세포, GABA, Glycine - 신경세포)

2) 만성염증 치료 - fasting, 항염증 herbal(항염방), --> 문치연 자율신경 자극치료법(T5-9 전침, 미주신경 전침)

3) senescent cell(cell cycle arrest 세포, 좀비세포) synolytic therapy : 미토콘드리아 신생합성운동법, 발효 건생탕

   spermidine, NAD+ booster(나이아신 고농도)

4) rejuvenation therapy : 줄기세포 치료, 발효 회춘-재생탕(확정 아님)

https://www.youtube.com/watch?v=RXVDiW6aPaE&t=32s

위 영상에 위 글 내용에 metabolic reprogramming을 위한 구체적인 치료내용을 넣어야!!

아래 논문의 내용을 통합해서...

Orthomolecular 관점에서 senolytic therapy는
영양소와 천연 화합물을 최적화하여
세포 노화를 유발하는 노화세포(senescent cells)를 선택적으로 제거하거나 억제하는 접근을 의미.

이는
비타민, 플라보노이드, 폴리페놀 등의 영양소를 고용량으로 활용하여
세포 건강을 회복시키는 데 초점을 맞춥니다.

아래에서 최신 논문(주로 2024-2025년)을 기반으로 주요 영양소와 치료제를 설명.

각 논문의 핵심 발견과 orthomolecular적 적용을 요약하며,
관련 영양소(예: quercetin, fisetin, curcumin, resveratrol, NAD+ boosters)를 중점으로 다루었습니다. 

1. Quercetin (케르세틴) Orthomolecular 관점에서 quercetin은 양파, 사과 등에서 추출되는 플라보노이드로, 항산화 및 항염증 효과를 통해 노화세포를 제거하는 대표적 senolytic 영양소입니다. 고용량 보충(예: 500-1000mg/일, 주기적 투여)이 세포 생존 경로(BCL-2)를 억제하여 SASP(노화 관련 분비 phenotype)를 줄이는 데 효과적입니다.

• 최신 논문: "Senolytics as Modulators of Critical Signaling Pathways: a Promising Strategy to Combat Brain Aging and Neurodegenerative Disorders" (2025, Neurochem Res) 이 논문은 quercetin과 dasatinib의 조합(D+Q)이 노화세포를 제거하여 알츠하이머병 같은 신경퇴행성 질환에서 공간 기억력을 개선한다고 보고합니다. Orthomolecular적으로 quercetin은 천연 영양소로, ROS(활성산소종) 축적을 줄여 미토콘드리아 기능을 강화하며, 고용량 보충이 조직 항상성을 유지하는 데 유용합니다. 쥐 모델에서 4개월간 투여 시 노화 마커가 감소했습니다.
• 최신 논문: "Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics" (2025, Drug Des Devel Ther) 여기서는 quercetin이 사과·양파에서 유래한 천연 화합물로, ROS가 풍부한 노화세포의 apoptosis(세포 사멸)를 촉진하여 SASP 사이토카인을 줄인다고 강조합니다. Orthomolecular 치료제로, curcumin과 병용 시 염증을 감소시키고 조직 기능을 향상시킵니다. 동물 모델에서 건강 수명을 연장하는 잠재력을 보였습니다.

2. Fisetin (피세틴) Fisetin은 딸기, 사과 등에서 얻어지는 플라보노이드로, orthomolecular적으로 강력한 senolytic으로 평가됩니다. NF-κB 신호를 억제하여 산화 스트레스를 줄이고, 노화세포를 광범위하게 제거합니다. 주기적 고용량(예: 100-200mg/일, 2일 연속 후 휴식)이 권장됩니다.

• 최신 논문: "Modeling treatment of osteoarthritis with standard therapy and senolytic drugs" (2025, PLoS One) 이 연구는 fisetin이 노화 연골세포를 제거하여 관절염 진행을 늦춘다고 모델링했습니다. Orthomolecular 관점에서 UC-II(콜라겐 보충)와 병용 시 시너지 효과가 나타나 E-efficacy(효능 지수)를 높입니다. 임상 1상 시험에서 40-80세 참가자에서 100mg/일 투여로 부작용 없이 WOMAC 점수(통증 평가)가 개선되었으며, 6개월간 연골 퇴화를 지연시켰습니다.
• 최신 논문: "Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients' treatment" (2024, npj Aging) Fisetin의 senolytic 활동이 in vitro 스크리닝에서 발견되었으며, in vivo에서 프로게로이드 쥐 모델의 노화세포 축적을 줄였다고 합니다. Orthomolecular적으로 신장 섬유화나 근육 위축증 치료에 유용하며, SARS-CoV-2 감염 시 노화세포 제거로 사망률을 낮췄습니다. 천연 폴리페놀로서 면역요법으로의 발전 가능성을 제안합니다.

3. Curcumin (커큐민) Curcumin은 강황에서 추출되는 폴리페놀로, orthomolecular에서 항산화 영양소로 사용되며, SASP 분비를 억제하고 산화 스트레스를 줄이는 senolytic입니다. 아날로그(EF24) 형태로 강화되어 사용됩니다.

• 최신 논문: "Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells" (2025, Nutrients) 이 리뷰는 curcumin이 노화세포를 표적으로 심혈관 질환을 완화한다고 설명합니다. Orthomolecular 관점에서 영양 intervention으로, 노화세포 축적을 줄여 CVD(심혈관 질환) 발생을 억제합니다. 천연 제품으로서 염증과 apoptosis를 조절하며, 연구 방법으로 영양 보충의 잠재력을 강조합니다.
• 최신 논문: "Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics" (2025, Drug Des Devel Ther) Curcumin의 플라보노이드 특성이 SASP를 억제하고 염증을 줄여 조직 기능을 개선한다고 합니다. Orthomolecular 치료제로 quercetin과 병용 시 시너지 효과가 나타나며, 동물 모델에서 수명을 연장합니다.

4. Resveratrol (레스베라트롤) 및 NAD+ Boosters (니코틴아미드 리보사이드 등) Resveratrol은 포도, knotweed에서 유래한 폴리페놀로, SIRT1과 AMPK를 활성화하여 미토콘드리아 건강을 촉진합니다. NAD+ boosters는 세포 에너지를 보충하는 orthomolecular 영양소로, 노화세포를 간접적으로 억제합니다.

• 최신 논문: "Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics" (2025, Drug Des Devel Ther) Resveratrol이 SIRT1을 활성화하여 미토콘드리아 기능을 개선하고 노화 시작을 지연시킨다고 합니다. NAD+ boosters(니코틴아미드 모노뉴클레오티드 등)는 미토콘드리아 건강을 강화하여 동물 모델에서 수명을 연장합니다. Orthomolecular적으로 영양 보충으로 활용됩니다.
• 최신 논문: "Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction" (2024, Endocr Rev) Senolytics가 당뇨, 비만 등 내분비 장애를 치료한다고 하며, resveratrol과 NAD+ boosters가 노화세포를 제거하여 HRT(호르몬 대체 요법) 대안으로 제안됩니다. 임상 시험에서 노화세포 부담 감소를 추적하는 패널이 개발되었습니다.

고농도 나이아신(niacin, 비타민 B3)은 주로 니코틴산(nicotinic acid, NA) 또는 니코틴아미드(nicotinamide, NAM) 형태로 사용되며, NAD+ (니코틴아미드 아데닌 디뉴클레오티드) 전구체로서 세포 내 NAD+ 수준을 증가시켜 노화세포(senescent cells)의 기능을 개선하거나 축적을 완화하는 역할을 합니다. 이는 직접적인 senolytic(노화세포 사멸 유도) 효과라기보다는 senomorphic(노화세포의 해로운 표현형 억제) 효과에 가깝습니다. 기전으로는 NAD+ 증가를 통해 SIRT1/3(시르투인) 활성화, 미토콘드리아 기능 강화, ROS(활성산소) 감소, 산화 스트레스 완화, SASP(노화 관련 분비 표현형) 억제가 주요합니다. 

1. NAD+ 수준 증가를 통한 미토콘드리아 기능 개선 및 ROS 감소 기전

고농도 나이아신은 Preiss-Handler 경로나 salvage 경로를 통해 NAD+를 보충하여 노화세포의 미토콘드리아 손상을 복구하고, 산화 스트레스를 줄입니다. 이는 노화세포 축적을 간접적으로 억제합니다.

• 논문: "Supplementation of Nicotinic Acid and Its Derivatives Up-Regulates Cellular NAD+ Level Rather than Nicotinamide Derivatives in Cultured Normal Human Epidermal Keratinocytes" (2024, Life) 이 연구는 인간 표피 각질형성세포(keratinocytes)에서 고농도 NA(10μM)가 세포 내 NAD+ 수준을 1.3배 증가시킨다고 보고합니다. 기전: NA가 NAPRT1(니코틴산 포스포리보실트랜스퍼라제 1)을 통해 NAMN(니코틴산 모노뉴클레오티드)으로 전환되어 de novo 경로로 NAD+ 합성을 촉진합니다. 이는 NAMPT 억제제(FK866)에 의한 NAD+ 고갈을 6시간 내 회복시킵니다. 추가로, NA는 미토콘드리아 SOD2(슈퍼옥사이드 디스뮤타제 2)와 SIRT3(시르투인 3) 단백질을 상향 조절하여 미토콘드리아 ROS 축적을 억제합니다(SOD2 p<0.05). 고농도(30-100μM)에서 약간 역전되지만, 전체적으로 NAD+ 감소로 인한 미토콘드리아 기능 저하(노화 과정에서 발생)를 완화하여 세포 노화(senescence)를 지연시킵니다. 이는 inflammaging(염증성 노화)을 억제하는 메커니즘으로 작용합니다.
• 논문: "Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation" (2021, Antioxidants) NAM이 피부 노화 제어에서 NAD+ 대사를 조절하여 세포 NAD+ 풀을 회복시킨다고 설명합니다. 기전: NAM이 NAMPT 활성을 강화하고 미토콘드리아 ROS 생성을 줄여 세포 수명을 연장합니다. 노화 피부 섬유아세포에서 NAM은 미토콘드리아 전자 전달 체계를 복원하고, 산화 스트레스 하에서 해당(glycolysis)을 보호합니다. 고농도 NAM은 SASP 관련 염증(예: IL-6, TNF-α)을 억제하여 노화세포의 해로운 영향을 완화하며, senolytic-like 효과로 UV 유발 apoptosis를 보호하고 표피 줄기세포 증식을 유지합니다. 이는 노화세포 제거가 아닌 표현형 억제(senomorphic)를 통해 피부 재생을 촉진합니다.

2. SIRT1 활성화와 NAMPT 탈아세틸화를 통한 NAD+ 항상성 회복 나이아신은 SIRT1을 활성화하여 NAMPT(니코틴아미드 포스포리보실트랜스퍼라제)를 탈아세틸화하고, NAD+ 합성을 증가시켜 노화 관련 증상을 개선합니다.

• 논문: "Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity" (2023, Nature Communications) 비록 니코틴(nicotine)에 초점이 맞춰져 있지만, NAD+ 전구체로서 나이아신과 유사한 기전을 공유합니다. 저용량 니코틴(1-10ng/mL)이 SIRT1과 NAMPT 결합을 촉진하여 NAMPT를 탈아세틸화하고, NAD+ 합성을 증가시킵니다. 이는 노화세포에서 NAD+ 감소를 방지하고, β-NMN 수준을 높여 에너지 대사 장애를 완화합니다. 결과: 신경염증 억제(JAK2/STAT3 경로), 산화 스트레스 감소(단백질 카르보닐 감소, SOD 활성 증가), 텔로미어 단축 방지. 쥐 모델에서 인지 저하 지연과 노화 증상 개선. 나이아신의 경우도 NAD+ 보충으로 유사 효과가 기대되며, 고농도에서 senescence 관련 미토콘드리아 결함을 수정합니다.

3. 항산화 효과와 senescence 표현형 억제 고농도 나이아신은 ROS 수준을 직접 억제하여 노화세포의 senescence 마커를 줄입니다.

• 논문: "Nicotinamide Exerts Antioxidative Effects on Senescent Cells" (2015, Mol Cells; 2023-2024 업데이트 참조) NAM이 노화 MCF-7 세포에서 ROS 증가를 억제하고, senescence 표현형(예: β-갈락토시다제)을 줄입니다. 기전: NAM이 항산화제로 작용하여 지질·단백질 산화, DNA 손상, 세포막 탈분극, apoptosis를 방지합니다. 고농도 NAM은 NAD+ 소비 효소(PARP, CD38)를 억제하여 NAD+ 풀을 유지하고, senescence 유발을 막습니다. 이는 노화세포 제거가 아닌 기능 회복을 통해 전체 조직 노화를 완화합니다.

스페르미딘이 autophagy를 자극하는 주요 메커니즘

• Epigenetic 조절: 히스톤 아세틸화를 억제하여 autophagy 관련 유전자(LC3, Beclin-1 등)를 활성화합니다.
• AMPK 및 TFEB 경로 활성화: 에너지 센서 AMPK를 자극하고, autophagy 마스터 조절자인 TFEB를 핵으로 이동시켜 autophagy flux(자기포식 흐름)를 증가시킵니다.
• 미토콘드리아 품질 관리(mitophagy): 손상된 미토콘드리아를 선택적으로 제거하여 ROS(활성산소)를 줄이고, 세포 에너지 항상성을 유지합니다.
• Nrf2 경로: 산화 스트레스 방어 유전자를 활성화하여 간접적으로 autophagy를 지원합니다.

이러한 메커니즘으로 스페르미딘은 autophagy inducer로서 노화 억제(geroprotective) 효과를 발휘하며, fasting(단식)이나 칼로리 제한의 주요 매개체로도 작용합니다(2024 Nature Cell Biology 연구에서 fasting-mediated autophagy가 spermidine 의존적임이 확인됨).
노화세포(senescent cells)에서의 구체적 효과 노화세포는 autophagy가 저하되어 손상된 단백질·오가넬라가 축적되고, SASP(염증성 분비 phenotype)를 통해 주변 조직에 만성 염증을 유발합니다. 스페르미딘은 이를 다음과 같이 개선합니다:

• Autophagy 복원으로 senescence 완화 노화 내피세포(Endothelial cells)에서 spermidine 보충 시 autophagy와 mitophagy가 증가하여 혈관 형성(angiogenesis) 능력이 회복되고, 노화 마커(p16, SA-β-gal)가 감소합니다(2023 Scientific Reports, 2024-2025 후속 연구 참조).
• 면역세포 senescence 감소 건강한 고령자 대상 연구(2025 preprint 및 2026 업데이트)에서 spermidine 보충(예: 1-3mg/일)이 림프구의 p16 발현을 줄이고, B세포에서 autophagic flux와 TFEB 타겟 유전자를 크게 증가시켰습니다. 결과적으로 백신 반응(특히 SARS-CoV-2)이 향상되었으며, senescent immune cells가 "rejuvenated(젊어짐)"되었습니다.
• 피부·연골·뇌 등 조직 수준 senescent 섬유아세포에서 spermidine이 autophagy를 촉진해 세포 증식을 회복하고 피부 노화 징후를 개선합니다(2025 고스퍼미딘 효모 연구). 관절염 연골세포에서도 autophagy를 복원해 NF-κB 신호를 억제하고 SASP를 줄입니다. 뇌 노화 모델(SAMP8 쥐)에서 spermidine + spermine이 autophagy를 유도해 산화 스트레스와 미토콘드리아 기능을 개선합니다.
• Senomorphic 효과 중심 스페르미딘은 전형적인 senolytic(노화세포 직접 사멸)보다는 senomorphic(노화세포의 해로운 phenotype을 억제)로 분류

Review Article

Open Access

Regulation of Immune Cell Functions by Metabolic Reprogramming

Jaehong Kim

First published: 13 February 2018

https://doi.org/10.1155/2018/8605471Digital Object Identifier (DOI)

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Academic Editor: Abdallah Elkhal

This article is part of Special Issue: 

• Impact of Metabolism on Immune Responses

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Abstract

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

초록 (Abstract)

최근 연구 결과에 따르면

면역 세포의 대사 상태가

면역 반응을 결정짓는 중요한 요인임이 밝혀졌다.

이전에는 암세포에서만 관찰되는 것으로 여겨졌던

호기성 해당(aerobic glycolysis)과 산화적 인산화(oxidative phosphorylation) 간의

대사 재프로그래밍(metabolic reprogramming)이,

암 이외의 다양한 병리적 조건에서

여러 유형의 면역 세포 및 기질 세포(stromal cells)에서도 발생한다.

암, 비만 지방 조직, 상처 치유 조직의 미세환경은

염증 반응이라는 공통된 특징을 공유한다.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4036716/

Chronic Inflammation and Cytokines in the Tumor Microenvironment - PMC

https://www.nature.com/articles/s41392-021-00658-5

또한,

대식세포(macrophages)와 T 세포의 대사 변화는

이제 면역 세포의 기능적 가소성(functional plasticity)에 결정적이며,

암을 비롯한 많은 병리 과정의 진행과 회귀에 책임이 있는 것으로 간주되고 있다.

다른 세포 구성 요소들에 의해 유도된 미세환경의 대사 변화가

면역 세포의 기능적 가소성을 유발할 가능성이 있다.

본 총설에서는

대식세포와 T 세포에서 일어나는 대사 재프로그래밍의 분자 기전을 탐구하며,

특히 종양 미세환경(tumor microenvironment)을 중심으로

미세환경의 대사 변화가 면역 세포의 기능 조절에 미치는 최근 업데이트를 요약한다.

1. 서론 (Introduction)

1. Introduction

Pleiotropic interactions between various cells are responsible for the maintenance and disturbance of homeostasis in the tissue microenvironment of physiological and pathological conditions. For example, from early carcinogenesis to progression and metastasis, cancer cells interact with various types of stromal cells, for example, cancer-associated fibroblasts, endothelial cells, and immune cells in the tumor microenvironment (TME). The TME is flooded with cytokines and growth factors responsible for “smoldering persistent inflammation.” This reactive stroma is a well-characterized component of the TME that shows similarities to the repair response in injured tissue [1]. Recent findings revealed that various immune cell subsets are dominant regulators of the delicate balance between homeostasis and disturbance in the tissue microenvironment [2–5]. For example, macrophages can form a major component of immune cell infiltrate in the TME, constituting as much as half of a tumor mass [6, 7]. Immune responses of M1 and M2 macrophages describe the opposing activities of killing or repairing. The typical M1 macrophages drive inflammation and show high antigen presentation, high production of inflammatory cytokines such as IL-12 and IL-23, and high production of nitric oxide (NO) and reactive oxygen intermediates. In contrast, M2-type responses are the “resting” phenotype and are observed in the resolution of inflammation without infections, tissue remodeling, and repair. It has been widely accepted that IFNγ alone or with microbial LPS or cytokines such as GM-CSF and TNF induces classically activated M1 macrophages, and IL-4, IL-6, IL-10, IL-13, IL-21, IL-33, immune complexes, and Notch can induce the M2 form of macrophage activation [8, 9]. Notably, truly polarized macrophages are rare [10–13] and tumor-associated macrophages (TAMs) can be also described as M(IL-4), M(Ig), M(IL-10), M(GC: glucocorticoid), M(IFNγ), M(LPS), and so forth, according to a recently attempted nomenclature based on specific activation standard [12]. Evidence supports a tumor-promoting role of TAMs, and high frequencies of TAMs are generally associated with poor prognosis in most human cancers [2, 14, 15]. TAMs infiltrating established tumors generally show the properties of an M2-like activated anti-inflammatory, protumoral properties rather than M1-like activated proinflammatory, antitumoral phagocytic properties [16–18].

Macrophages can also form a major component of immune cell infiltrate in obese adipose tissue (AT), constituting as much as 40% of all AT cells [19]. In the progression of obesity, a switch from M2-like to M1-like activation of the macrophage population occurs and inflammatory cytokines such as tumor necrosis factor (TNF) contribute to insulin resistance in adipocytes characterized by an impaired insulin response such as hypertriglyceridemia and elevated fasting glucose [20, 21]. In addition, lymphoid as well as myeloid cells infiltrates and expands in the liver tissue and the obese AT and these immune cell subsets are responsible for the development of obesity-related metabolic dysregulation due to excessive nutrient intake and exacerbation of low-grade inflammatory changes in the microenvironment. CD8+ T cells also promote inflammation and metabolic disturbance in the AT [22]. In addition to macrophages and T cells, neutrophils and mast cells can also disturb the homeostasis in the tissue microenvironment.

Many recent findings in the field of immunometabolism now show that metabolic status in immune cells can determine various types of immune responses. Immune cells have remarkably diverse functions and cellular activities that are associated with distinct metabolic demands. The traditional simple concept of production of cellular ATP is that glycolysis generates two molecules of ATPs from one molecule of glucose. Glycolysis metabolizes glucose to pyruvate first, and the pyruvate is further metabolized to carbon dioxide, NADH, and FADH2 in the mitochondria. The reducing equivalents (NADH and FADH2) drive oxidative phosphorylation (OXPHOS) for more ATP synthesis. In the 1920s, it was demonstrated that cancer tissues can metabolize, even in aerobic conditions, about tenfolds more glucose to produce lactate than normal tissues can and this is known as aerobic glycolysis or the Warburg effect [23]. Since pyruvate is metabolized to lactate and secrete, lactate appears to be wasted in aerobic glycolysis. However, lactate secretion out of cells allows increased continuous glucose influx from the generation of NAD+ and resultant accumulation of glycolytic intermediates facilitates biomass synthesis for rapidly proliferating cells. Since the observation and dramatic revitalization of the Warburg effect, the dominant glycolysis and relatively reduced OXPHOS were thought to be confined to cancer cells. However, recent findings clearly show that the Warburg effect-like metabolic reprogramming also exists in rapidly proliferating cells including various types of immune cells, most notably in macrophages and T cells, and determines the function of the immune cell subsets in disease conditions such as those in inflamed tissue or cancer [24–27].

조직 미세환경의 생리적 및 병리적 조건에서

항상성(homeostasis)의 유지와 교란은

다양한 세포들 간의 다면적 상호작용(pleiotropic interactions)에 의해 결정된다.

예를 들어,

초기 발암부터 진행 및 전이에 이르기까지

암세포는 종양 미세환경(TME) 내

암 관련 섬유아세포(cancer-associated fibroblasts),

내피세포(endothelial cells),

면역 세포 등 다양한 기질 세포와 상호작용한다.

TME는

“지속적인 저등급 염증(smoldering persistent inflammation)”을 유발하는

사이토카인과 성장인자로 가득 차 있다.

이러한 반응성 기질(reactive stroma)은

손상된 조직의 회복 반응과 유사한 잘 알려진 TME의 구성 요소이다 [1].

최근 연구들은

다양한 면역 세포 하위 집단이

조직 미세환경에서 항상성과 교란 사이의 섬세한 균형을 조절하는

주요 조절자임을 밝혀냈다 [2–5].

예를 들어,

대식세포는 TME 내 면역 세포 침윤의 주요 구성 요소로,

종양 질량의 절반에 이를 수 있다 [6, 7].

M1 및 M2 대식세포의 면역 반응은

염증 살상(killing) 또는 회복(repairing)이라는 상반된 활성을 나타낸다.

전형적인 M1 대식세포는

염증을 유도하며,

높은 항원 제시 능력, IL-12 및 IL-23과 같은

염증성 사이토카인 고생산, 산화질소(NO) 및 활성산소 중간체 고생산을 특징으로 한다.

반면 M2형 반응은

“휴지” 표현형으로,

감염이 없는 염증 해소, 조직 재형성 및 회복 과정에서 관찰된다.

IFNγ 단독 또는 미생물 LPS나 GM-CSF, TNF와 같은 사이토카인과 함께하면

전형적으로 활성화된 M1 대식세포가 유도되며,

IL-4, IL-6, IL-10, IL-13, IL-21, IL-33,

면역 복합체, Notch 등은 M2형 활성화를 유도한다 [8, 9].

그러나

실제로 완전히 극성화된(polarized) 대식세포는 드물며 [10–13],

종양 관련 대식세포(TAMs)는

최근 제안된 특정 활성화 기준에 따른 명명법으로

M(IL-4), M(Ig), M(IL-10), M(GC: glucocorticoid), M(IFNγ), M(LPS) 등으로 분류될 수 있다 [12].

증거들은 TAMs의 종양 촉진 역할을 뒷받침하며,

대부분의 인간 암에서 TAMs의 높은 빈도는 일반적으로 불량한 예후와 관련된다 [2, 14, 15].

Tumour-associated macrophages as treatment targets in oncology.pdf

780.77KB

확립된 종양에 침윤하는 TAMs는

일반적으로 M1-like 활성화된 염증성·항종양 식세포 작용보다는

M2-like 활성화된 항염증·종양 촉진 특성을 보인다 [16–18].

대식세포는

비만 지방 조직(AT)에서도 면역 세포 침윤의 주요 구성 요소로,

전체 AT 세포의 최대 40%를 차지할 수 있다 [19].

비만 진행 과정에서 대식세포 집단은

M2-like에서 M1-like 활성화로 전환되며,

종양괴사인자(TNF)와 같은 염증성 사이토카인이

지방세포의 인슐린 저항성(insulin resistance)을 유발하여

고중성지방혈증(hypertriglyceridemia) 및 공복 혈당 상승 등의 특징을 보인다 [20, 21].

또한,

비만 AT와 간 조직에서는 림프구 및 골수계 세포가 침윤·증식하며,

이러한 면역 세포 하위 집단은

과도한 영양 섭취로 인한 비만 관련 대사 이상과 미세환경의 저등급 염증 변화를 악화시킨다.

CD8+ T 세포 역시

AT에서 염증과 대사 장애를 촉진한다 [22].

대식세포와 T 세포 외에도

호중구(neutrophils)와 비만세포(mast cells)

역시 조직 미세환경의 항상성을 교란할 수 있다.

최근 면역대사학(immunometabolism) 분야의 많은 발견은

면역 세포의 대사 상태가 다양한 면역 반응을 결정한다는 것을 보여준다.

면역 세포는

매우 다양한 기능과 세포 활동을 가지며,

이는 뚜렷한 대사 요구와 연관된다.

전통적인 세포 ATP 생산 개념은

해당과정(glycolysis)이

한 분자의 포도당으로부터 두 분자의 ATP를 생성한다는 단순한 것이었다.

해당과정은

포도당을 피루브산(pyruvate)으로 대사한 후,

피루브산은 미토콘드리아에서 이산화탄소, NADH, FADH2로 추가 대사된다.

이 환원당등(NADH와 FADH2)이

산화적 인산화(OXPHOS)를 통해

더 많은 ATP 합성을 유도한다.

1920년대에 암 조직은

호기성 조건에서도

정상 조직보다 약 10배 많은 포도당을 젖산(lactate)으로 대사한다는 사실이 밝혀졌으며,

이는 호기성 해당 또는 Warburg 효과로 알려져 있다 [23].

피루브산이 젖산으로 대사되어 분비되기 때문에

젖산은 호기성 해당에서 낭비되는 것으로 보인다.

그러나

세포 외로의 젖산 분비는

NAD+ 생성을 통해 지속적인 포도당 유입을 가능하게 하고,

해당 중간체의 축적은 빠르게 증식하는 세포의 바이오매스 합성을 촉진한다.

Warburg 효과의 관찰과 극적인 재조명 이후,

우세한 해당과 상대적으로 감소된 OXPHOS는 암세포에 국한된 것으로 여겨졌다.

그러나

최근 연구들은 빠르게 증식하는 세포들,

특히 대식세포와 T 세포를 포함한 다양한 면역 세포에서도

Warburg 효과와 유사한 대사 재프로그래밍이 존재하며,

이는 염증 조직이나 암과 같은 질환 상태에서

면역 세포 하위 집단의 기능을 결정짓는다는 것을 명확히 보여준다 [24–27].

2. Metabolic Regulation of Macrophage Phenotypes

The function of macrophages is not limited to the maintenance of homeostasis in the tissue microenvironment but also includes many activities such as cytokine production and phagocytosis upon their activation. Importantly, macrophages are famous for their plasticity and adoption of various activation states in response to their functional requirements signaled from their microenvironment. For example, an innate arm of the immune system can have an important capacity to adapt after challenged with pathogens [28]. This is known as innate immune memory or trained immunity. Trained immunity from epigenetic reprogramming of macrophages shows high glucose consumption and a high ratio of NAD+ to its reduced form NADH, reflecting a shift in metabolism with an increase in glycolysis and M1-like activation of macrophages, dependent on the activation of mTOR through the Akt-HIF-1α pathway [29]. M2-like activated macrophages exploit fatty acid oxidation (FAO) to fuel OXPHOS rather than aerobic glycolysis for ATP production [30–32].

Of note, HIF1α and NFκB drive the M1 phenotypes [33, 34] and PGC1β, and peroxisome proliferator-activated receptors and STAT6 drive the M2 phenotypes (Figure 1) [35–38]. Phosphorylation and activation of a nutritional sensor, AMPK, regulate mitochondrial biogenesis via deacetylation of regulating proteins, including SIRT1 with NAD+, and suppress HIF1α and NFκB [38–40]. AMPK and NAD+-SIRT1-PGC1β signaling are key factors for nutritional state-dependent M1/M2-like activation of macrophages in inflammatory conditions [39, 41]. HIF-1α also enhances the lactate dehydrogenase- (LDH-) mediated conversion of pyruvate-to-lactate [42] and increases expression‎ of GLUT1, GLUT3, and MCT4 to increase glucose uptake and expression‎ of pyruvate kinase M2 (PKM2), resulting in an increase in the secretion of lactate and uncoupled glycolysis and oxidative phosphorylation [43, 44] (Figure 2). Pyruvate dehydrogenase (PDH) inactivation from phosphorylation by pyruvate dehydrogenase kinases (PDKs) prevents pyruvate from entering the mitochondrial Krebs cycle [45]. HIF-1α transcriptionally activates the PDKs [46, 47].

2. 대식세포 표현형의 대사 조절 (Metabolic Regulation of Macrophage Phenotypes)

대식세포의 기능은

조직 미세환경의 항상성 유지에 국한되지 않고,

활성화 시 사이토카인 생산과 식세포작용(phagocytosis)을 포함한 다양한 활동을 수행한다.

특히 대식세포는

미세환경으로부터 전달되는 기능적 요구 신호에 따라

다양한 활성화 상태를 채택하는 뛰어난 가소성(plasticity)으로 유명하다.

예를 들어,

선천 면역계는 병원체에 노출된 후 적응할 수 있는 중요한 능력을 갖추고 있으며 [28],

이는 선천 면역 기억(innate immune memory)

또는 훈련 면역(trained immunity)으로 알려져 있다.

대식세포의 후성유전학적 재프로그래밍(epigenetic reprogramming)을 통한

훈련 면역은

높은 포도당 소비와

NAD+ 대 환원형 NADH의 높은 비율을 보이며,

이는 Akt-HIF-1α 경로를 통한 mTOR 활성화에 의존하는

해당과정(glycolysis) 증가 및 M1-like 대식세포 활성화를 반영한다 [29].

반면

M2-like로 활성화된 대식세포는

ATP 생산을 위해 호기성 해당(aerobic glycolysis)보다는

지방산 산화(FAO)를 활용하여

산화적 인산화(OXPHOS)를 주 에너지원으로 삼는다 [30–32].

주목할 점은

HIF1α와 NFκB가 M1 표현형을 주도하며 [33, 34],

PGC1β, peroxisome proliferator-activated receptors(PPARs), STAT6가

M2 표현형을 주도한다는 것이다 (그림 1) [35–38].

영양 센서인 AMPK의 인산화 및 활성화는

SIRT1을 포함한 조절 단백질의 탈아세틸화(deacetylation)를 통해

NAD+와 연계되어 미토콘드리아 생합성(mitochondrial biogenesis)을 조절하며,

HIF1α와 NFκB를 억제한다 [38–40].

AMPK와 NAD+-SIRT1-PGC1β 신호 전달은

염증 조건에서 영양 상태에 의존적인

대식세포의 M1/M2-like 활성화의 핵심 인자이다 [39, 41].

HIF-1α는

또한 젖산 탈수소효소(LDH)를 매개로 한 피루브산에서 젖산으로의 전환을 강화하며 [42],

GLUT1, GLUT3, MCT4의 발현을 증가시켜 포도당 흡수를 촉진하고,

pyruvate kinase M2(PKM2)의 발현을 증가시켜 젖산 분비를 높이며,

결과적으로 해당과정과 산화적 인산화가 분리(uncoupled)되는 상태를 유도한다 [43, 44] (그림 2).

피루브산 탈수소효소(PDH)는

피루브산 탈수소효소 키나아제(PDK)에 의한 인산화로 비활성화되며,

이로 인해 피루브산이 미토콘드리아 크렙스 회로(Krebs cycle)에 진입하지 못하게 된다 [45].

HIF-1α는

전사적으로 PDK를 활성화한다 [46, 47].

Figure 1

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Regulation of metabolic rewiring in macrophages. PGC1 is important for FAO and mitochondrial biogenesis (shown in blue) and HIF1α for aerobic glycolysis (shown in red). Active SIRT1 can inhibit inflammation and glycolytic metabolism and promote mitochondrial biogenesis and FAO. Interaction of PD-L1 and PD-1 induces FAO and suppresses aerobic glycolysis and immune functions in Teff. PD-1: programmed death-1; PD-L1: programmed death ligand-1; RTK: receptor tyrosine kinase; TEFF: effector T cell.

Figure 2 (a)

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Metabolism of glucose and fatty acid at a glance. (a) Stabilization of HIF-1α upregulates GLUTs, HK2, PFK2, PKM2, LDH, PDK, and MCT4 shown in red. ACC: acetyl-CoA carboxylase; ARG: arginase; CPT-1: carnitine palmitoyltransferase 1; FAT: fatty acid translocase; G3P: glyceraldehyde 3-phosphate; GLUT: glucose transporter; HK2: hexokinase 2; IDH: isocitrate dehydrogenase; LCFacyl-CoAs: long-chain fatty acyl-CoAs; MCT: monocarboxylate transporter; 2PG: 2-phosphoglycerate; 3PG: 3-phosphoglycerate; PEP: phosphoenolpyruvate; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PFK: phosphofructokinase; PS: pyruvate symporter; SDH: succinate dehydrogenase; TAG: triacylglyceride; TCAT: tricarboxylic acid transporter. (b) A schematic of the Krebs cycle and metabolites exported out of the mitochondria. Arginine is metabolized to urea and ornithine in M2-like macrophages that do not express NOS. ARG: arginase; NOS: nitric oxide synthase.

Figure 2 (b)

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Metabolism of glucose and fatty acid at a glance. (a) Stabilization of HIF-1α upregulates GLUTs, HK2, PFK2, PKM2, LDH, PDK, and MCT4 shown in red. ACC: acetyl-CoA carboxylase; ARG: arginase; CPT-1: carnitine palmitoyltransferase 1; FAT: fatty acid translocase; G3P: glyceraldehyde 3-phosphate; GLUT: glucose transporter; HK2: hexokinase 2; IDH: isocitrate dehydrogenase; LCFacyl-CoAs: long-chain fatty acyl-CoAs; MCT: monocarboxylate transporter; 2PG: 2-phosphoglycerate; 3PG: 3-phosphoglycerate; PEP: phosphoenolpyruvate; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PFK: phosphofructokinase; PS: pyruvate symporter; SDH: succinate dehydrogenase; TAG: triacylglyceride; TCAT: tricarboxylic acid transporter. (b) A schematic of the Krebs cycle and metabolites exported out of the mitochondria. Arginine is metabolized to urea and ornithine in M2-like macrophages that do not express NOS. ARG: arginase; NOS: nitric oxide synthase.

LPS-activated dendritic cells and M1-like activated macrophages show enhanced aerobic glycolysis, flux through the pentose phosphate pathway, and fatty acid synthesis but have incomplete OXPHOS at the level of succinate dehydrogenase (SDH) and isocitrate dehydrogenase, blocking the synthesis of mitochondrial ATP. In these cells, glucose is used for the biosynthesis of large quantities of cytokines and effector molecules, and inactivation of OXPHOS directs metabolites from the Krebs cycle for inflammatory reaction [32, 48]. Accumulation of succinate and citrate from the truncated OXPHOS leads to stabilization of HIF1α by limiting prolyl hydroxylase activity to maintain a proinflammatory, antitumoral response [49–51].

Recently, itaconic acid-mediated inhibition of SDH has also been found as a driver for succinate accumulation in LPS-stimulated M1-like activated proinflammatory macrophages [52]. Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation and Irg1 gene silencing in macrophages results in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections [53].

High intracellular iron levels in M1-like activated macrophages stabilize HIF1α through low levels of ferroportin and high levels of H-ferritin, involved in iron export and storage, respectively [54, 55]. Hemeoxygenase-1 (HO-1) catabolizes heme to ferrous ion, biliverdin, and carbon monooxide, and suppression of HO-1 results in M2-like activation of TAMs [56].

HIF1α can also be stabilized from nitrosylation with peroxynitrites from increased iNOS [57], favoring aerobic glycolysis in M1 phenotypes. NFκB transcriptionally activates proinflammatory genes including iNOS, which forms NO in the presence of arginine. Peroxynitrite, formed from NO and superoxide anions in the mitochondria, nitrosylates iron-sulfur proteins in the mitochondrial electron transport chain, and the resultant nitrosylation can inhibit OXPHOS [58], also favoring aerobic glycolysis in M1 phenotypes. Unlike iNOS-mediated catabolism of arginine to NO in M1-like activated macrophages, M2-like activated macrophages catalyze arginine to urea and ornithine by arginase 1 (ARG1); ARG1 is a representative marker for M2-like activation. As NO production is limited in M2-like activated macrophages, the nitrosylation-mediated inhibition of OXPHOS is dampened, now favoring M2 phenotypes [48]. Although HIF1α drives the M1 phenotypes in hypoxic conditions, lactate produced by cancer cells, as a by-product of aerobic glycolysis, has an unexpected critical function in HIF1α-dependent expression‎ of ARG1 and resultant M2-like activation of TAMs in normoxic conditions [59] (Figure 3). These findings clearly indicate highly interconnected signaling for the conservation of HIF-1-centered metabolic phenotypes.

Figure 3 (a)

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Metabolic changes in the TME-regulating immune cell function. (a) Lactate produced by cancer cells, as a by-product of aerobic glycolysis, has a critical function in inducing M2-like activation of TAMs. (b) A low-glucose microenvironment via multiple signaling pathways regulates activation state of macrophages and T cells. TCR: T cell receptor; VEGF: vascular endothelial growth factor.

Figure 3 (b)

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Metabolic changes in the TME-regulating immune cell function.

(a) Lactate produced by cancer cells, as a by-product of aerobic glycolysis, has a critical function in inducing M2-like activation of TAMs.

(b) A low-glucose microenvironment via multiple signaling pathways regulates activation state of macrophages and T cells. TCR: T cell receptor; VEGF: vascular endothelial growth factor.

As stated, M2-like activated macrophages show lowered glycolysis and enhanced FAO to fuel OXPHOS. Th2 cytokine and IL-4-induced PGC1β increase mitochondrial biogenesis and FAO in a STAT6-dependent manner [38, 41, 60]. PGC1β plays a key role in increasing mitochondrial biogenesis and OXPHOS by upregulating the expression‎ of FAO-involved genes [41]. IL-4-/IL-13-stimulated macrophages express PFKFB1, which produces a low level of a glycolytic activator, fructose 2,6 bisphosphate [61, 62]. In IL-4-stimulated macrophages, fatty acid sources such as LDL and VLDL are taken up via the scavenger receptor CD36 and metabolized in the lysosome. The CD36-mediated lysosomal lipolysis is essential for the M2-like activation [31].

An orphan nuclear receptor, estrogen-related receptor α (ESRRα), is required for the increased mitochondrial biogenesis [63]. Importantly, ESRRα-deficient macrophages show a decrease in phagosomal maturation and antimicrobial activity [64]. Another study reported an M1-like phenotype of increased glycolysis but impaired mitochondrial respiratory function and biosynthesis as a result of ESRRα deficiency [65]. Interestingly, VLDLR expression‎ is a determinant factor in inflammation and in M1-like activation of macrophages in AT [66].

In spite of our knowledge gained from macrophages in inflammatory disease conditions, our understanding of the metabolic regulations in TAMs is surprisingly limited and the signals involved in communication between tumors and macrophages are still poorly defined [67]. However, emerging evidence strongly indicates that the metabolic reprogramming of macrophages is closely related to the protumoral or antitumoral function of macrophages [68, 69] and that unraveling the TAM phenotype might lead to the identification of alternative, novel metabolic targets for TAM-directed intervention. Recently, it was shown that lactate produced by cancer cells has a critical function in inducing M2-like activation of TAMs [59] (Figure 3). Acidification of the TME by lactate increases level of ARG1, a representative M2 marker, in macrophages, which limits the proinflammatory, antitumoral response of TAMs and, importantly, the proliferation and activation of T cells [59, 70]. Also, de novo fatty acid synthesis in cancer cells increases fatty acid levels in the TME to promote the generation of immunosuppressive, regulatory T cells (Tregs) and M2-like TAMs, favoring survival of cancer cells [71]. Expression‎ level of vitamin D receptor (VDR) negatively correlates with metastasis in breast cancer, and suppression of VDR by TNFα can mediate the prometastatic effects of TAMs through enhancement of the β-catenin pathway [72].

3. Metabolic Regulation of T Cells

Multiple studies have shown that distinct metabolic programs in CD4+ T cell subsets can be manipulated in vivo to control Treg and effector T cells (TEFF) development in inflammatory diseases [73–76]. A transcription factor, Myc, shows a dominant role in driving metabolic reprogramming in activated T cells by promoting glycolysis and glutaminolysis and suppressing FAO [75]. mTOR increases expression‎ of HIF-1α, which facilitates the expression‎ of critical glycolytic enzymes and promotes differentiation and activation of T cells [76].

A “shift” from OXPHOS to aerobic glycolysis is a hallmark of T cell activation [25]. T cells, if not activated, show low levels of metabolic requirements, use OXPHOS to maximize production of ATP as an energy source, and engage scarcely in biosynthesis, while activated T cells use aerobic glycolysis to produce effector molecules for rapid cellular proliferation [32].

In order to facilitate proper immunological response upon encounter of antigenic stimuli, it is vital that T cells should differentiate into TEFF and clonally expand rapidly to ensure prompt reaction. Glycolysis promotes the differentiation of activated CD4+ T cells into TEFF [73]. Activated T cells also consume glutamine to fuel the Krebs cycle to support the production of biomass and ATP [77]. Clonal expansion is achieved from upregulation of glycolysis and OXPHOS together. In addition to high level of glycolysis, increased mitochondrial flux and production of ROS are also required for initiation of the clonal expansion [78]. After differentiation, TEFF cells, Th1, Th2, and Th17 cells, remain highly glycolytic [73].

When the antigenic stimuli are eliminated, most TEFF cells die, leaving behind a small antigen-specific T cell population that becomes memory T cells (Tm). Quiescent Tm with the CD8 coreceptor exploits FAO to fuel OXPHOS rather than aerobic glycolysis for ATP production [32, 73]. Instead of utilizing extracellular lipids for energy generation, Tm metabolizes de novo generated fatty acids, synthesized from extracellular glucose and intracellularly stored during the previous effector phase [79]. Enforcing FAO with activation of AMPK or inhibiting mTOR results in increased numbers of Tm [80–82]. Mitochondrial oxidative metabolism supports immunosuppression and lineage commitment of Tregs [83–85]. Tregs with increased glycolysis are more proliferative yet have reduced ability to maintain FOXP3 expression‎ and suppress inflammation [84].

4. Nonmetabolic Function of Glycolytic Enzymes in Immune Cells

In addition to their canonical, metabolic functions in glycolysis, recent studies uncovered nonmetabolic functions of glycolytic enzymes such as hexokinase 2 (HK2), phosphoglucose isomerase, and GAPDH, connecting metabolic states to apoptosis, gene transcription, protein kinase activity, and the mTOR signaling pathway [86]. Briefly, the interaction between HK2 and voltage-dependent anion channel (VDAC1) reduces the release of proapoptotic proteins and prevents cancer cells from undergoing apoptosis [87]; phosphoglucose isomerase exerts its antiapoptosis effect by suppressing the expression‎ of Apaf-1 and caspase-9 genes, thereby indirectly regulating the formation of the apoptosome [88, 89]. GAPDH exerts controversial pro- and antiapoptotic effects through interaction with VDAC1 and induction of autophagy, respectively [86, 90].

Other studies have shown that GAPDH, HK, and enolase are also RNA-binding proteins [91–93] and the “REM (RNA–enzyme–metabolite) hypothesis” proposes a regulatory interaction between gene expression‎ and cellular metabolism by RNA-binding metabolic enzymes [94, 95]. It is notable that many glycolytic enzymes, formerly known to exclusively function in glycolytic metabolic events in the cytoplasm or mitochondria, have now been shown to regulate transcription and translation [86, 91]. Indeed, numerous metabolic enzymes that also function in glycolysis, fatty acid synthesis, and the Krebs cycle are also RNA-binding proteins [96], although the significance for immune response is not clearly known except for that of GAPDH [95] and enolase [32, 83]. Recently, a REM connection with GAPDH was proven in T cell activation [25]. GAPDH is diverted to glycolysis and translation of IFNγ and IL-2 is not perturbed in highly glycolytic T cells. However, when aerobic glycolysis is blocked, GAPDH binds to IFNγ and IL-2 mRNA in CD4+ T cells to suppress their translation [25]. In myeloid cells, GAPDH is a component of the IFNγ-activated inhibitor of translation (GAIT) complex that controls translation of inflammatory genes [97, 98]. High glycolytic flux suppresses the interaction between GAPDH and Rheb and thus allows Rheb to activate mTORC1 and stimulate cell growth [99]. By modulating expression‎ of Foxp3-splicing variants with exon 2(Foxp3-E2), enolase-1-mediated glycolysis controls induction of human Tregs with a potent immunosuppressive function [83]. When glycolysis is inhibited, enolase-1 translocates to the nucleus and represses expression‎ of the Foxp3-E2 splice variant in Tregs and suppresses Treg induction.

The level of the glycolytic intermediate phosphoenolpyruvate (PEP) is controlled by a balance between enolase-mediated formation of PEP and pyruvate kinase-mediated conversion to pyruvate. PKM2 exists either as an inactive dimer or as more active tetramer, and the transition between the two conformations is subject to posttranslational modifications [100]. Dimeric PKM2, previously regarded as crucial for metabolic reprogramming exclusively in cancer cell, is also important in promoting aerobic glycolysis in immune cells [101, 102]. Enhanced expression‎ of dimeric PKM2 reduces the rate of PEP conversion to pyruvate and results in an accumulation of glycolytic products that can be otherwise metabolized in biosynthetic pathways [32]. Importantly, PEP enhances antitumor effector functions in activated T cells by regulating Ca2+ import into the endoplasmic reticulum, thus sustaining translocation of nuclear factor of activated T cells (NFAT) into the nucleus and the expression‎ of a set of genes that are required for T cell activation [103].

These findings imply that a direct and strong interaction exists between the nonmetabolic function of glycolytic enzymes and the generation of immune responses and also that enhanced glycolysis sustains antitumoral and proinflammatory functions via highly interconnected signaling in immune cells.

5. Metabolic Changes in the TME Influencing Immune Cell Functions

The microenvironment determines the metabolism of immune cells, which in turn adjust to a broad spectrum of configurations to meet the demands of various cellular activities. For example, changes in the metabolic profiles of immune cells by cancer cells can alter the function of the immune cells [103, 104]. A protracted aerobic glycolysis acidifies and destabilizes the TME and this is consistent with the view of the tumor as an unhealed wound [105]. Similarities of utilizing nutrients and engaging metabolic regulation to sustain cellular proliferation and survival are shared by cancer and immune cells. Notably, nutritional competition between cancer cells and antitumoral immune cells in the TME shifts the activation and differentiation status of T-cells to favoring the survival of cancer cells [103, 104, 106, 107].

Recently, it was shown that lactate produced by cancer cells, as a by-product of aerobic glycolysis, has a critical function in signaling that induces M2-like activation of TAMs [59] (Figure 3). Interestingly, lactate-induced M2-like activation was from HIF1α-dependent expression‎ of ARG1. Depletion of glucose and a glucose-rich hypoxic ROS environment favor M2-like activation and M1-like activation of TAMs, respectively, and depletion of glucose can disarm T cells in the TME [27, 104]. Low levels of ATP from dietary restrictions or energy consumption induces nicotinamide phosphoribosyltransferase that generates NAD+, which is a key factor for SIRT1 activation. SIRT1 acetylates and activates PGC1β to increase OXPHOS [35, 67, 108]. Pyruvate is metabolized by LDH-A, producing lactate and NAD+. NAD+ acts as an electron acceptor in the Krebs cycle and the electron transport system in mitochondria. It appears feasible from these findings that glucose-depleted, low ATP, and NAD+-rich states (in cachexic patient with advanced cancer) may drive the M2-like activation of macrophages, while the macrophage population still retains its phagocytic activity in maintaining biosynthesis with molecules acquired from their microenvironment [32]. For the identification of alternative, novel targets for TAM-directed intervention, it would be necessary to show whether these events can predominantly happen in TAMs of the TME.

A recent study observed that hypoxia-induced upregulation of the immunosuppressive programmed death ligand-1(PD-L1) is directly mediated by HIF1α [109]. In the TME, cancer cells, macrophages, and dendritic cells express PD-L1, a notable ligand for immune checkpoint, programmed cell death-1(PD-1) in TEFF. The interaction of PD-1 and PD-L1 directly inhibits glycolysis and promotes lipolysis and FAO in T cells, resulting in failure of the antitumoral function of T cells [110] (Figure 1). The lessons that application of immune checkpoint blockade antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), PD-1, and PD-L1, which are used clinically, restore glucose in the TME, permitting T cell glycolysis and IFNγ production clearly show that nutrient availability in the microenvironment can change the metabolic status of immune cells. Another study also revealed that PD-1 expression‎ by TAMs correlates with protumoral activity, and blockage of PD-1–PD-L1 in vivo increases phagocytosis, reduces growth of cancer cells, and increases the survival of mice in mouse models of cancer in a macrophage-dependent way [111]. In addition, blocking PD-L1 directly on cancer cells decreases glycolysis and restores glucose in the TME, resulting in allowance of antitumoral function of T cells from glycolysis and IFNγ production [104].

In conclusion, these findings indicate that signals such as cytokines, growth factors, hypoxia, and nutrient availability that emanate from the microenvironment can induce metabolic changes in immune cell subsets, resulting in changes in immune functions and pathological responses. An interesting perspective is whether immune cells can supply their microenvironment with lactate and antioxidative resources as stromal cells in the TME are able to (the reverse Warburg effect). Considering their preponderance in the TME, there is an ample possibility that metabolic changes in a large subgroup of macrophages or T cells may also affect the metabolic state of their microenvironment and functions of other cellular components.

6. Potential Metabolic Targets for the Manipulation of Immune Cell Function

Since the function of immune cells is dependent on a delicate metabolic balance, results of many clinical trials performed with inhibitors of metabolic enzymes and oncogenes will provide valuable insights for the prospect of immunomodulation by specific metabolic regulation [112]. Of note, results from targeting cancer metabolism in vivo have been disappointing and less prominent than results from targeting immune cell metabolism [85]. The PKM2 inhibitor, TLN-232, was tested in a clinical trial for refractory renal cell carcinoma (NCT00422786). Inactive dimeric PKM2 activates the mTORC1 signaling pathway by phosphorylating the mTOR inhibitor, AKT1S1, and leads to an accelerated oncogenic growth and autophagy inhibition of cancer cells [113]. In line with this, increase in the tetrameric, active form of PKM2, attenuated the LPS-induced proinflammatory M1-like macrophage phenotypes while promoting M2-like macrophage phenotypes [114]. Many AMPK activators are now tested in clinical and preclinical studies for diabetes, cancer, and cardiovascular disease [115]. Importantly, AMPK stimulation inhibiting mTORC1 was sufficient to decrease Glut1 and increase generation of Tregs in an animal model, implying AMPK activation as a potential manipulable checkpoint for immune response [73]. REDD1, an inhibitor of mTOR, is highly expressed in M2-like TAMs. Inhibition of REDD1 stimulates glycolysis in the TAMs and competition of glucose between TAMs and endothelial cells prevents vascular hyperactivation and promotes the formation of quiescent vascular junctions in the TME [69]. Suppression of REDD1 was attempted in phase 2 clinical trial (NCT00713518) for the treatment of neovascularization in AMD patients. Nitrosylation of HIF1α prevents its degradation. If denitrosylation of HIF1α is observed, its modulation may be potentially applicable for the inhibition of glycolytic enzymes and the alleviation of M1-like phenotypes.

Isoprenylation of ubiquinone is important for OXPHOS and isoprenylation of Ras, Rho, and Rab guanosine triphosphatases is involved in immunological synapse formation, migration, proliferation, and cytotoxic effector response of T cells. The intracellular availability of sterols is crucial for isoprenylation modification of proteins for plasma membrane attachment and represents a checkpoint for metabolic reprogramming that modulates T cell responses [116]. Statin and other chemical inhibitors of the meval‎onate pathway can suppress isoprenylation of Rho proteins [117] and have been tested in many clinical trials.

Clinical trials involving agents that inhibit PD-L1 and PD-1 are now being performed. Atezolizumab is the sole member of this class currently approved for the treatment of bladder cancer, but approvals for avelumab, durvalumab, nivolumab, and pembrolizumab in the treatment of various cancer are anticipated in the near future [118]. Therefore, it appears possible that the combined use of metabolism-targeting reagents with immune checkpoint inhibitors can alter the activation and differentiation of T cells.

7. Conclusions

Immunity and metabolism advance together. Considering the significant contribution of immune cell functions in promoting and suppressing various types of disease progression, repolarization of immune cells from the potential targets stated above shows an ample possibility to become novel therapeutic approaches. Extension of our knowledge of the functional plasticity of macrophages and T cells spanning from inflammation biology to cancer immunology and the persistent reprogramming effect achievable from stable epigenetic changes in the metabolic pathways of macrophages [29] and potentially T cells by potential modulators may provide new information for immune therapeutic strategies applicable for different disease conditions. Importantly, cancer cells and host primary cell constituents such as immune cells and stromal cells can form microanatomical compartments within the cancer tissue to regulate metabolic needs, immune surveillance, survival, invasion, and metastasis. Indeed, different signals from particular locations in the TME seem to influence activation of TAMs and T cells and overall tumor prognosis [119]. TAMs can be diverse within the microanatomical compartments, including the accumulation of M1-like activated cells with protumoral properties in hypoxic areas [120] and differences in inflammatory components and pathways between tumors originating in distinct anatomical sites [120, 121]. The notion that metabolic competition between cancer cells, immune cells, and other stromal cells can determine function and fate of each cell subset proposing that identification of which of specific niches in the microenvironment can impede immune cells from proper metabolic engagement will encourage significant contributions to this research field. Generation of metabolically fit T cells prior to adoptive cell transfer will improve T cell-based immunotherapy against cancer by surviving the unfavorable, hostile TME. Furthermore, successful therapies targeting the function of macrophages and T cells will require identification of targets that specifically allow metabolic reprogramming of immune cells while, at the same time, not causing an increase in proliferation and survival of cancer cells or systemic inflammatory changes or autoimmunity. Our understanding of the metabolic regulations in B cells is surprisingly limited, and the mechanisms about how cellular metabolism supports and regulates function of B cells are still poorly defined. B cell immunometabolism is anticipated to become an exciting research field.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This study was supported by a grant of the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT (MSIT), Republic of Korea (1711045557, 1711045538, and 1711045554) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF of Korea) funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1D1A1B03029063).