Immunotherapeutic interventions are showing effectiveness across a wide range of cancer types, but only a subset of patients shows clinical response to therapy. Responsiveness to checkpoint blockade immunotherapy is favoured by the presence of a local, CD8+ T cell-based immune response within the tumour microenvironment. As molecular analyses of tumours containing or lacking a productive CD8+ T cell infiltrate are being pursued, increasing evidence is indicating that activation of oncogenic pathways in tumour cells can impair induction or execution of a local antitumour immune response. This Review summarizes our current knowledge of the influence of oncogenic effects on evasion of antitumour immunity.

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Impact of oncogenic pathways on evasion of antitumour immune responses

The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.

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Navigating metabolic pathways to enhance antitumour immunity and immunotherapy

Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes.

Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy

Glioma epigenetics: From subclassification to novel treatment options.

Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors. Given these findings, we have investigated the impact of IDH mutations on the immunological milieu in LGG. In immortalized normal human astrocytes (NHAs) and syngeneic mouse glioma models, the introduction of mutant IDH1 or treatment with 2HG reduced levels of CXCL10, which was associated with decreased production of STAT1, a regulator of CXCL10. Expression of mutant IDH1 also suppressed the accumulation of T cells in tumor sites. Reductions in CXCL10 and T cell accumulation were reversed by IDH-C35, a specific inhibitor of mutant IDH1. Furthermore, IDH-C35 enhanced the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. Our findings demonstrate a mechanism of immune evasion in IDH-MUT gliomas and suggest that specific inhibitors of mutant IDH may improve the efficacy of immunotherapy in patients with IDH-MUT gliomas.

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Nduka A. Amankulor

Papers

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas