Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Scharping, Nicole E.; Menk, Ashley V.; Whetstone, Ryan D.; Zeng, Xue; Delgoffe, Greg M.

doi:10.1158/2326-6066.cir-16-0103

Cited by 419 publications

(422 citation statements)

References 30 publications

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“…However, it is worth noting that many obese male melanoma patients in this clinical study received anti-diabetic drugs, 58 which have been shown to enhance the antitumor activity of anti-PD-1 blockade in preclinical melanoma models. 59,60 …”

Section: Discussionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Section: Discussionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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“…Similarly, stroma that has been glycolytically transformed with high MCT4 expression may be more resistant to drugs that alter the cellular redox state. Targeted therapy aimed at reducing OXPHOS with drugs such as arsenic or metformin in combination with other biologic agents such as PD1 inhibitors may be synergistic 3555 . Also, agents that inhibit the transport of lactate into HRS cells would cut the nutrient supply source to lymphoma cells, essentially starving the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment

Mikkilineni

Whitaker‐Menezes

Domingo‐Vidal

et al. 2017

Seminars in Oncology

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Background Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL since non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. Methods A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin bleomycin vinblastine and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from 4 subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1 and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in >50% of cells. Results TOMM20, MCT1 and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared to tumor associated macrophages (TAMs) and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1 while TAMs have absent expression of TOMM20 and MCT1 in all but 2 cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but 1 case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenviro...

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“…Although no detailed clinical studies examining influences of metformin on more subtle aspects of immune function have been carried out, laboratory studies [34][35][36][37][38][39][40][41][42][43][44][45] have provided considerable evidence for a variety of immunomodulatory effects.…”

Section: Metformin and The Immune Systemmentioning

confidence: 99%

“…While the notion that metformin may influence immune function as a consequence of altering energy metabolism in the many cell lineages that comprise the immune system is straightforward, it is unclear what subpopulations of immune cells are most affected by the drug, and therefore what the net effect on immune function would be in different clinical contexts. Recent results in tumour immunology provide examples of enhanced immune function as a consequence of metformin exposure [36][37][38], while studies in other contexts, including tuberculosis and multiple sclerosis, suggest anti-inflammatory actions [40][41][42][43][44][45].…”

Section: Metformin and The Immune Systemmentioning

confidence: 99%

“…Of potential clinical relevance is the finding in this study of phenformin enhancement of the tumour-inhibitory effect of anti-programmed cell death protein 1 (PD-1) antibody therapy on growth of the Braf(V600E)/Pten null melanoma mouse model, such that the combination of phenformin and the antibody cooperatively induces CD8 + T cell infiltration. Another study [38] also documented enhancement of PD-1 blockade as a cancer immunotherapy, but attributed this to a mechanism involving reduction of tumour hypoxia by the biguanide, which in turn was attributed to reduced oxygen consumption secondary to inhibition of oxidative phosphorylation. Effects of metformin on immunologic memory have been associated with enhanced efficacy of an anti-tumour vaccine in a laboratory model, with a significant effect on host survival [35].…”

Section: Metformin and The Immune Systemmentioning

confidence: 99%

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The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.

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Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Cited by 419 publications

References 30 publications

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment

The effects of metformin on gut microbiota and the immune system as research frontiers

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