Can tumor cells take it all away?

[문형철]

Tumor cells utilize glucose to engage in aerobic glycolysis, fulfilling their metabolic demands for extensive proliferation. A recent study in Nature discovers that tumor-infiltrating myeloid cells exhibit a superior glucose uptake capacity over tumor cells, which present enhanced glutamine metabolism, suggesting that nutrient partitioning in the TME might be more complex than previously thought.

종양 세포는 포도당을 사용하여 호기성 해당 작용에 참여하여 광범위한 종양세포 증식에 대한 대사 요구를 충족시킴. Nature의 최근 연구에 따르면 종양 침윤 골수 세포(tumor-infiltrating myeloid cells)가 종양 세포보다 우수한 포도당 흡수 능력을 나타내고, 글루타민 대사가 향상되는 것으로 보아, TME의 영양소 분배가 이전에 생각했던 것보다 더 복잡할 수 있음을 시사함.

Main text

Tumor cells take up enormous amounts of glucose and undergo enhanced glycolysis even under aerobic conditions (known as aerobic glycolysis or the Warburg effect) (Vander Heiden et al., 2009). Although inefficient in ATP production, aerobic glycolysis generates building blocks that support extensive proliferation of tumor cells. As a consequence of elevated glucose consumption by tumor cells, the glucose level in the tumor interstitial fluid decreases while lactate accumulates (Sullivan et al., 2019).

종양 세포는 엄청난 양의 포도당을 흡수하고, 호기성 조건(호기성 해당 작용 또는 Warburg 효과로 알려짐)에서도 강화된 해당 작용을 겪습니다(Vander Heiden et al., 2009). ATP 생산에는 비효율적이지만, 호기성 해당작용은 종양 세포의 광범위한 증식을 지원하는 빌딩 블록을 생성합니다. 종양 세포에 의한 증가된 포도당 소비의 결과로, 젖산이 축적되는 동안 종양 간질액의 포도당 수준이 감소합니다(Sullivan et al., 2019).

Moreover, increased tumor glycolytic activity is negatively correlated with T cell infiltration in human cancers, and inhibiting tumor glycolysis significantly enhances the T cell anti-tumor response in preclinical models (Cascone et al., 2018). These metabolic features of tumor cells support the currently prevailing notion that the tumor microenvironment ( TME ) can be a metabolically restricted milieu for infiltrating immune cells, thereby promoting immune evasion by inducing T cell dysfunction (Ho et al., 2015).

더욱이, 증가된 종양 해당 작용 활성은 인간 암에서 T 세포 침윤과 음의 상관 관계가 있으며, 종양 해당 작용을 억제하면 전임상 모델에서 T 세포 항종양 반응이 크게 향상됩니다(Cascone et al., 2018). 종양 세포의 이러한 대사적 특징은 종양 미세 환경(TME)이 면역 세포에 침투하기 위한 대사적으로 제한된 환경이 될 수 있고, 이에 따라 T 세포 기능 장애를 유도함으로써 면역 회피를 촉진할 수 있다는 현재 널리 퍼진 개념을 뒷받침합니다.

In the recent work, Reinfeld et al., 2021 made use of the positron emission tomography (PET) tracer 18F-fluorodeoxyglucose (FDG) to measure glucose uptake of tumor cells and tumor-infiltrating immune cells in MC38 and CT26 mouse tumor models. The authors reveal that not only tumor cells, but also tumor-infiltrating immune cells, in particular tumor-infiltrating myeloid cells (TIMs), are able to take up significant amounts of glucose within the TME. Interestingly, TIMs exhibit the highest capacity to take up glucose among TME-resident tumor cells and other immune cell types (Figure 1), presumably due to their elevated mTOR activation and increased expression‎ of glucose transporter 1 (GLUT1) and hexokinase.

최근 연구에서 Reinfeld et al., 2021은 양전자 방출 단층 촬영(PET) 추적자 18F-플루오로데옥시글루코스(FDG)를 사용하여 MC38 및 CT26 마우스 종양 모델에서 종양 세포 및 종양 침윤 면역 세포의 포도당 흡수를 측정했습니다. 저자는 종양 세포뿐만 아니라 종양 침윤 면역 세포, 특히 종양 침윤 골수 세포(TIM)도 TME 내에서 상당한 양의 포도당을 흡수할 수 있음을 밝혔습니다. 흥미롭게도 TIM은 TME 상주 종양 세포 및 기타 면역 세포 유형 중에서 포도당을 흡수하는 가장 높은 용량을 나타냅니다(그림 1). 이는 아마도 증가된 mTOR 활성화 및 포도당 수송체 1(GLUT1) 및 헥소키나제의 발현 증가 때문일 것입니다.

Overall, TIMs seem to be particularly metabolically active as they also display the highest glycolytic and mitochondrial activities among TME-resident cells. Targeting glycolysis by mTORC1 inhibition significantly suppresses the metabolic activity of TIMs, but not tumor cells, suggesting that TIMs are more sensitive to mTOR inhibition compared to tumor cells. Despite their lower glucose capacity per cell, in this study tumor cells were found to consume up to 60% of the available glucose, due to their predominant presence in the TME, while TIMs with a higher glucose capacity accounted for 30% of the glucose uptake within the tumor. Similarly, tumor cells have been found to possess the highest glutamine uptake capacity and are responsible for the majority of glutamine consumption within the TME. Thus, tumor cells are indeed the dominant glucose and glutamine consumers within the TME, closely followed by TIMs. Thus, the authors propose the idea that immune cells selectively take up nutrients based on cell-intrinsic programs rather than being determined by nutrient limitation in the TME.

전반적으로, TIM은 TME 상주 세포 중에서 가장 높은 해당작용 및 미토콘드리아 활성을 나타내기 때문에 특히 대사적으로 활성인 것으로 보입니다. mTORC1 억제에 의한 해당 작용을 표적으로 하는 것은 TIM의 대사 활성을 유의하게 억제하지만 종양 세포는 억제하지 않으며, 이는 TIM이 종양 세포에 비해 mTOR 억제에 더 민감함을 시사한다. 세포당 낮은 포도당 용량에도 불구하고, 이 연구에서 종양 세포는 TME에 주로 존재하기 때문에 이용 가능한 포도당의 최대 60%를 소비하는 것으로 밝혀졌습니다. 반면 높은 포도당 용량을 가진 TIM은 포도당 섭취의 30%를 차지했습니다 종양 내. 유사하게, 종양 세포는 가장 높은 글루타민 흡수 능력을 갖고 TME 내에서 대부분의 글루타민 소비를 담당하는 것으로 밝혀졌습니다. 따라서 종양 세포는 실제로 TME 내에서 지배적인 포도당 및 글루타민 소비자이며 TIM이 그 뒤를 잇습니다. 따라서 저자는 면역 세포가 TME의 영양 제한에 의해 결정되기 보다는 세포 고유 프로그램을 기반으로 선택적으로 영양소를 흡수한다는 아이디어를 제안합니다.

Notably, inhibition of glutamine transport resulted in an increase in glucose uptake in all cell populations within the TME. Thus, glutamine restriction, a promising approach to treat cancer (Leone et al., 2019), might act partially through boosting glucose uptake of tumor-infiltrating immune cells.

특히, 글루타민 수송의 억제는 TME 내의 모든 세포 집단에서 포도당 흡수의 증가를 초래했습니다. 따라서 암 치료에 대한 유망한 접근 방식인 글루타민 제한(Leone et al., 2019)은 종양 침윤 면역 세포의 포도당 흡수를 증가시켜 부분적으로 작용할 수 있습니다. 

Intriguingly, Reinfeld et al. reported that glucose and lactate levels are similar between healthy kidney tissue and renal carcinomas in human patients. This finding suggests that glucose deprivation and increased lactate abundance might not be general features in all tumor types. Furthermore, this study highlights the importance of the concept that tumor metabolic targeting might unexpectedly disturb the metabolic crosstalk between different cell populations within the TME, thus impacting the metabolic features and fitness of tumor-infiltrating immune cells.

흥미롭게도 Reinfeld et al. 건강한 신장 조직과 인간 환자의 신장 암종 사이에 포도당과 젖산 수치가 유사하다고 보고했습니다. 이 발견은 포도당 결핍과 증가된 젖산 풍부가 모든 종양 유형에서 일반적인 특징이 아닐 수 있음을 시사합니다. 또한, 이 연구는 종양 대사 표적이 TME 내의 다른 세포 집단 간의 대사 누화를 예기치 않게 방해하여 종양 침투 면역 세포의 대사 기능과 적합성에 영향을 줄 수 있다는 개념의 중요성을 강조합니다.

Figure 1Nutrient distribution in the tumor microenvironment

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T cell usage of glucose was documented decades ago (Frauwirth and Thompson, 2004), and glucose availability can regulate T cell effector function (Cham and Gajewski, 2005). With the notion of the Warburg effect, the availability of glucose to tumor-infiltrating cells, in particular T cells, has been the subject of many studies. In this study, Reinfeld et al. showed that tumor-infiltrating T lymphocytes (TILs) can obtain glucose in a comparable amount as tumor cells but higher than splenic T lymphocytes do in tumor mouse models, which raises a possibility that glucose competition between tumor cell and tumor-infiltrating T lymphocytes may not exist as previously reported (Chang et al., 2015).

포도당의 T 세포 사용은 수십 년 전에 문서화되었으며(Frauwirth and Thompson, 2004), 포도당 가용성은 T 세포 효과기 기능을 조절할 수 있습니다(Cham and Gajewski, 2005). Warburg 효과의 개념과 함께 종양 침윤 세포, 특히 T 세포에 대한 포도당의 가용성은 많은 연구의 주제였습니다. 이 연구에서 Reinfeld et al. 종양 침윤 T 림프구(TILs)는 종양 세포와 비슷한 양으로 포도당을 얻을 수 있지만 비장 T 림프구보다 더 많이 종양 마우스 모델에서 얻을 수 있으며, 이는 종양 세포와 종양 침윤 T 림프구 사이의 포도당 경쟁이 그렇지 않을 가능성을 높입니다. 이전에 보고된 바와 같이 존재합니다(Chang et al., 2015).

PET tracers, such as FDG, indicate the cell’s capacity of taking up glucose; however, since FDG is given in saturated amounts, FDG uptake does not reflect the nutrients typically available in the TME. Moreover, although TILs obtain glucose at a higher level compared to splenic T lymphocytes, it remains unknown whether TILs acquire glucose in a sufficient amount to support their actions in the TME . Considering the spatial distribution of immune cells and the altered vasculature in tumors, more detailed analyses to unveil the nature of metabolic crosstalk and competition between tumor and stromal cells would provide a critical foundation for deciphering the immunosuppressive features of the TME.

FDG와 같은 PET 추적자는 포도당을 흡수하는 세포의 능력을 나타냅니다. 그러나 FDG는 포화된 양으로 제공되기 때문에 FDG 섭취는 TME에서 일반적으로 사용할 수 있는 영양소를 반영하지 않습니다. 더욱이, TIL이 비장 T 림프구에 비해 더 높은 수준에서 포도당을 얻긴 하지만, TIL이 TME에서의 작용을 지원하기에 충분한 양으로 포도당을 획득하는지 여부는 아직 알려지지 않았습니다. 면역 세포의 공간적 분포와 종양의 변경된 혈관 구조를 고려할 때, 대사 누화의 특성과 종양과 기질 세포 간의 경쟁을 밝히기 위한 보다 자세한 분석은 TME의 면역 억제 기능을 해독하는 데 중요한 기반을 제공할 것입니다.

Taken together, Reinfeld et al. raise the notion that TME nutrients are not solely consumed by tumor cells, and different nutrients are not evenly partitioned among different TME-resident cell populations. This study further underpins the possibility that differential partitioning of glucose and other nutrients, among different immune cell subsets in tumors, may play a critical role in tailoring immune responses and the differentiation status of infiltrating immune cells. Thus, nutrient partitioning in the TME might be more complex than previously thought, and further considerations will have to be made to understand the metabolic interactions within tumors. Considering the heterogeneity of tumors between cancer types and patients, future studies will need to decipher how different cell subsets and different cellular compositions modulate metabolic dependencies and therapeutic outcomes of metabolic targeting. This will also help to tailor targeted therapies modulating immunometabolism within the TME.

Declaration of interests

종합하면 Reinfeld et al. TME 영양소는 종양 세포에 의해서만 소비되지 않으며 다른 영양소는 다른 TME 상주 세포 집단 간에 고르게 분배되지 않는다는 개념을 제기합니다. 이 연구는 종양의 다른 면역 세포 하위 집합 사이에서 포도당 및 기타 영양소의 차등 분배가 면역 반응 및 침투 면역 세포의 분화 상태를 조정하는 데 중요한 역할을 할 수 있다는 가능성을 추가로 뒷받침합니다. 따라서 TME에서 영양소 분배는 이전에 생각했던 것보다 더 복잡할 수 있으며 종양 내 대사 상호작용을 이해하기 위해 추가 고려가 이루어져야 합니다. 암 유형과 환자 사이의 종양의 이질성을 고려할 때, 향후 연구는 다른 세포 하위 집합과 다른 세포 구성이 대사 의존성과 대사 표적의 치료 결과를 조절하는 방법을 해독해야 합니다. 이것은 또한 TME 내에서 면역대사를 조절하는 표적 치료제를 맞춤화하는 데 도움이 될 것입니다.

The authors declare no competing interests.

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