Identification of TRPM2 as a Potential Therapeutic Target Associated with Immune Infiltration: A Comprehensive Pan-Cancer Analysis and Experimental Verification in Ovarian Cancer

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Abstract

The exact role of Transient receptor potential melastatin 2 (TRPM2) in tumor progression and immunomodulation remains elusive. We comprehensively investigated the expression pattern, diagnostic value, prognostic impact, genetic and epigenetic alterations of TRPM2 in pan-cancer. Then, we explored underlying pathways associated with TRPM2 and immune-related signatures. Ovarian cancer (OV) specimens were enrolled to test the expression of TRPM2 by immunohistochemistry and RT-qPCR. OV cell A2780 transfected with shRNA targeting TRPM2 was used in subsequent experiments. TRPM2 was aberrantly expressed and associated with unfavorable prognosis across various cancers. It possesses significant diagnostic values with AUC > 0.90. TRPM2 participated in pathways mediating immunoregulation and tumorigenesis. The expression of TRPM2 was significantly correlated with tumor microenvironment scores, tumor-stemness index, macrophages infiltration, immune checkpoints, and immune-related genes. OV single-cell datasets also indicated that TRPM2 was predominantly distributed on macrophages and malignancies. The overexpressed TRPM2 in OV tissues was validated at both the mRNA and protein levels. TRPM2 expression was significantly correlated with type2 macrophage marker CD206. Knockdown of TRPM2 inhibited OV cell proliferation and promoted apoptosis. Overall, TRPM2 has relevance to an immunosuppressive tumor microenvironment by modulating macrophage. It could serve as a powerful biomarker for tumor screening and prognosis, and a potential therapeutic target for tumor treatment, especially for OV.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade.

Pornpimol Charoentong, Francesca Finotello, Mihaela Angelova … (2017)

The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.