Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

AbstractThe expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-associated neoantigens drive ICB responses in tumors with high mutational burden. In most patients, only a few of the mutations in the cancer exome that are predicted to be immunogenic are recognized by T cells. One factor that limits this recognition is the level of expression of the mutated gene product in cancer cells. Substantial preclinical data show that radiation can convert the irradiated tumor into a site for priming of tumor-specific T cells, that is, an in situ vaccine, and can induce responses in otherwise ICB-resistant tumors. Critical for radiation-elicited T-cell activation is the induction of viral mimicry, which is mediated by the accumulation of cytosolic DNA in the irradiated cells, with consequent activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) genes (STING) pathway and downstream production of type I IFN and other pro-inflammatory cytokines. Recent data suggest that radiation can also enhance cancer cell antigenicity by upregulating the expression of a large number of genes that are involved in the response to DNA damage and cellular stress, thus potentially exposing immunogenic mutations to the immune system. Here, we discuss how the principles of antigen presentation favor the presentation of peptides that are d...
Source: Genome Medicine - Category: Genetics & Stem Cells Source Type: research