Cancer Induced Immunosuppression And Its Modulation By Signal Inhibitors

Although cancer immunotherapy has recently demonstrated durable responses even in patients with advanced cancer, not all patients or cancer types respond to the therapy. Pretreatment immune status varies among cancer patients and is correlated with responses to immunotherapy. Immune conditions may be defined by the balance of positive and negative pathways in the anti-tumor immune responses, which are regulated by both cancer cell characteristics and patients' immune-reactivity along with various environmental factors. Gene alterations and signal activation define the immunological characteristics of cancer cells; tumor specific peptides derived from passenger mutations induce anti-tumor T-cells and oncogene activation (e. g. driver mutations, overexpression: MAPK, STAT3, NF-kappa B, beta-catenin) rather promote immunosuppression. Oncogene/signal activation in cancer cells triggers multiple immunosuppressive cascades involving various immunosuppressive molecules and cells (e. g. TGF-beta, IL10, IL6, VEGF, Treg, MDSC). Signal inhibitors are able to augment anti-tumor T-cell responses through multiple mechanisms including inhibition of cancer-induced immunosuppression, immunogenic cancer cell death, and enhancement of immune cell functions. Since the oncogene-signal activation status is different among patients, personalized immunotherapy combined with appropriate signal inhibitors may be considered for the development of effective immunotherapy.