Language：English   Publishing type：Research paper (scientific journal)  

To achieve sustained antitumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFNγ and proliferate robustly within the local tumor tissue upon antigen recognition. IFNγ production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic downregulation in tumor cells; in contrast, the agents trigger sustained antitumor immunity by upregulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.

DOI： 10.1093/intimm/dxab067

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Metformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated. METHODS: MitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer. RESULTS: Met administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs. CONCLUSIONS: We found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs' proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.

DOI： 10.1136/jitc-2021-002954

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Metformin, a drug for type 2 diabetes, also exerts anticancer effects. This study addressed the immunological effects of metformin on peritoneal dissemination. MATERIALS AND METHODS: We developed a mouse model of peritoneal dissemination via intraperitoneal injection of RLmale1, an X-ray-induced leukemia cell line, into BALB/c mice. Cell-surface markers, cytokine production, and myeloid-derived suppressor cells (MDSCs) were examined in cells from spleen and peritoneal lavage fluid. RESULTS: Metformin-treated mice exhibited suppressed intraperitoneal tumor growth and extended survival, and these effects were lost in mice with severe combined immunodeficiency. MDSCs induction was inhibited in metformin-treated mice. Although MDSC mobilization into the peritoneal cavity was correlated with suppression of interferon-γ production by tumor-infiltrating lymphocytes, the T-helper 1 ability of these lymphocytes was preserved in metformin-treated mice. CONCLUSION: Our findings demonstrate the action of metformin on both intraperitoneal tumors and immune-suppressive cells and might contribute to the development of immunotherapy against peritoneal dissemination.

DOI： 10.21873/anticanres.13652

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Language：English   Publishing type：Research paper (scientific journal)  

CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors.

DOI： 10.1093/intimm/dxy079

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8(+) tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8(+) TILs capable of producing multiple cytokines were mainly PD-1(-)Tim-3(+), an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8(+) TIL multifunctionality. The adoptive transfer of antigen-specific CD8(+) T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8(+) T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment.

DOI： 10.1073/pnas.1417636112

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Publisher：Okayama Medical Association  

DOI： 10.4044/joma.134.73

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：(株)羊土社  

免疫治療を実施した患者の腫瘍組織において、T細胞が浸潤しているにもかかわらず腫瘍免疫が破綻している例がある。その一因として腫瘍局所における持続的な抗原刺激による免疫疲弊が考えられるが、近年、T細胞の代謝変化が免疫疲弊を誘導するとの報告もあり、有効な免疫治療を行うためには免疫細胞そして腫瘍細胞の代謝状態を把握し、それぞれの代謝を腫瘍退縮に有利な方向へと制御することが重要である。本稿では腫瘍微小環境における免疫細胞、腫瘍細胞の代謝について理解を深め、さらにその制御法についても解説する。(著者抄録)

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Language：Japanese   Publisher：医歯薬出版(株)  

腫瘍局所は低酸素、高乳酸による低pH、さらに低栄養といった特殊な環境を構築している。エフェクター細胞が機能を発揮するためには栄養、とくにグルコースを必要としている。皮肉なことに、腫瘍細胞も大量にグルコースを消費し、増大する。このように腫瘍微小環境においては、エフェクター細胞と腫瘍との間にグルコースの奪い合い、すなわち代謝競合が起こっている。競合に負けたエフェクター細胞は次第にその機能を失い、腫瘍は増大へと向かう。このように代謝が腫瘍の運命を決定付けているということは興味深い知見である。見方を変えれば、個々の細胞の代謝を上手く制御することができれば腫瘍退縮へと導くことが可能となり、代謝制御は新たな免疫治療のターゲットとなりうる可能性がある。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00060&link_issn=&doc_id=20201005020007&doc_link_id=%2Faa7ayuma%2F2020%2F027501%2F008%2F0042b0048%26dl%3D3&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2020%2F027501%2F008%2F0042b0048%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (other)  

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Language：Japanese   Publisher：(株)羊土社  

腫瘍微小環境では免疫細胞と腫瘍細胞の間で栄養素、特にグルコースをめぐる激しい攻防を繰り広げており、代謝競合に負けた免疫エフェクター細胞は本来の機能を失い、その結果、腫瘍は増大へと向かう。これは腫瘍微小環境下の細胞の代謝が腫瘍の運命を決定することを示唆している。このような背景から近年、腫瘍を制圧するために代謝制御を視野に入れた治療が重要であるとの概念が広がってきた。本稿では腫瘍微小環境に存在する免疫細胞そして腫瘍細胞の代謝についての理解を深め、腫瘍免疫における代謝制御による治療法について解説する。(著者抄録)

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(株)羊土社  

免疫療法において腫瘍に対する免疫応答は患者体内で誘導されるが、腫瘍局所ではその機能が十分に発揮できないことが問題となっている。その一因として腫瘍局所は持続的な抗原刺激に加え、免疫抑制的な環境にあり、腫瘍免疫において要となるCD8+T細胞が疲弊状態に陥りその機能を発揮できないことが考えられる。したがって有効な免疫治療を行うためにはCD8+T細胞の状態を把握し、腫瘍局所においてその機能を維持させることが重要である。本稿では主に腫瘍免疫におけるCD8+T細胞の機能制御について免疫疲弊そして免疫代謝の観点から解説する。(著者抄録)

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Language：Japanese   Publisher：日本がん免疫学会  

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