Interplay between Immune Checkpoint Proteins and Cellular Metabolism

Lim, Sung‐Jig; Phillips, Joshua B.; Silva, Luciana Madeira da; Zhou, Ming; Fodstad, Øystein; Owen, Laurie B.; Tan, Ming

doi:10.1158/0008-5472.can-16-1647

Cited by 81 publications

(56 citation statements)

References 41 publications

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“…Recently, PDL1 has been reported to be involved in the regulation of tumor glucose metabolism [ 20 ]. Chang CH et al found that blocking PDL1 dampened tumor glycolysis by inhibiting mTOR activity and decreasing the expression of glycolysis enzymes [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

Huang

Xie

Wang

et al. 2017

J Exp Clin Cancer Res

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BackgroudThe purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.MethodsWestern blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC.ResultsWe found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.ConclusionsThis study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

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Section: Discussionmentioning

confidence: 99%

PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

Huang

Xie

Wang

et al. 2017

J Exp Clin Cancer Res

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“…Immunotherapy is in the ascendency with the Nobel prize in 2018 awarded for basic immunological discoveries that culminated in extremely successful checkpoint inhibitor therapies for cancer. At least part of their mechanism of action is the restoration of metabolic function in exhausted T cells, illustrating the importance of metabolic fitness of immune cells for effective immunotherapy (24,25). Our data on NK cells adds to this emerging paradigm and has implications for NK cell based immunotherapies.…”

Section: Discussionmentioning

confidence: 81%

TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

Slattery

Zaiatz-Bittencourt

Woods

et al. 2019

Preprint

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Natural Killer (NK) cells provide important protection from cancer and are a key requirement for particular immunotherapies. In activated NK cells, a metabolic response towards increased glycolysis and oxidative phosphorylation is crucial for NK cell effector functions. However, there is accumulating evidence that NK cells become dysfunctional during chronic inflammatory diseases, such as human breast cancer. This dysfunction is apparent in peripheral blood NK cells and can impact on normal NK cell immune responses and their effective targeting during immunotherapy. Herein, we demonstrate that prolonged cytokine stimulation combined with metabolic restriction, through inhibition of mTORC1, is sufficient to induce persistent dysfunction in human NK cells. TGFβ, also restricted NK cell metabolism and promoted persistent NK cell dysfunction. NK cells from patients with metastatic breast cancer had profound metabolic defects in glycolysis and mitochondrial function, and clear structural differences in NK cell mitochondrial morphology. Importantly, blocking elevated TGFβ improved readouts of metabolism and restored IFNγ production in patient NK cells.

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“…In addition, several pathways that have been recently proposed as mechanisms of response or resistance to anti-PD-1 therapy were also identified by our approach (data not shown), such as cellular metabolism [51], DNA damage/repair pathways [52], and defective transcription elongation [53].…”

Section: Resultsmentioning

confidence: 99%

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

Wang

Livingston

et al. 2020

Preprint

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24 Background: Despite remarkable success, only a subset of cancer patients have shown benefit from the anti-PD1 25 therapy. Therefore, there is a growing need to identify predictive biomarkers and therapeutic combinations for 26 improving the clinical efficacy. 27Results: Based upon the hypothesis that aberrations of any gene that are close to MHC class I genes in the gene 28 network are likely to deregulate MHC I pathway and affect tumor response to anti-PD1, we developed a network 29 approach to infer genes, pathway, and potential therapeutic target genes associated with response to PD-1/PD-L1 30 checkpoint immunotherapies in cancer. Our approach successfully identified genes (e.g. B2M and PTEN) and 31 pathways (e.g. JAK/STAT and WNT) known to be associated with anti-PD1 response. Our prediction was further 32 validated by 5 CRISPR gene sets associated with tumor resistance to cytotoxic T cells. Our results also showed that 33 many cancer genes that act as hubs in the gene network may drive immune evasion through indirectly deregulating 34 the MHC I pathway. The integration analysis of transcriptomic data of the 34 TCGA cancer types and our prediction 35 reveals that MHC I-immunoregulations may be tissue-specific. The signature-based score, the MHC I association 36 immunoscore (MIAS), calculated by integration of our prediction and TCGA melanoma transcriptomic data also 37 showed a good correlation with patient response to anti-PD1 for 354 melanoma samples complied from 5 cohorts. 38In addition, most targets of the 36 compounds that have been tested in clinical trials or used for combination 39 treatments with anti-PD1 are in the top list of our prediction (AUC=0.833). Integration of drug target data with our 40 top prediction further identified compounds that were recently shown to enhance tumor response to anti-PD1, such 41 as inhibitors of GSK3B, CDK, and PTK2. 42Conclusion: Our approach is effective to identify candidate genes and pathways associated with response to anti- 43PD-1 therapy, and can also be employed for in silico screening of potential compounds to enhances the efficacy of 44 anti-PD1 agents against cancer. 45 46 47 48 50 Breakthroughs in cancer immunotherapies have opened a new front in the war against cancer [1]. Instead of 51 directly targeting cancer cells using specific inhibitors, immunotherapies stimulate and modulate the host's 52 immune system to eliminate cancer cells. Recently, immune checkpoint blockade (ICB), which enhances T-cell 53 activity by inhibiting immunosuppressive checkpoint molecules such as cytotoxic T-lymphocyte-associated antigen 54 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), has produced 55remarkably durable responses in some cancer patients. Despite these successes, only a subset of cancer patients 56 benefits from these therapies, and rates of response vary widely among cancer types. Therefore, there is a growing 57 need to understand the mechanisms underlying this de novo resistance, to select predictive biomar...

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Interplay between Immune Checkpoint Proteins and Cellular Metabolism

Cited by 81 publications

References 41 publications

PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

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