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

TitleRadiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system.
Publication TypeJournal Article
Year of Publication2019
AuthorsLhuillier C, Rudqvist N-P, Elemento O, Formenti SC, Demaria S
JournalGenome Med
Date Published2019 06 20
KeywordsAnimals, Antigen Presentation, Antigens, Neoplasm, Humans, Mutation, Neoplasms, Radiotherapy

The 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 derived from newly synthesized proteins in irradiated cells. These concepts support a model that incorporates the presence of immunogenic mutations in genes that are upregulated by radiation to predict which patients might benefit from treatment with combinations of radiotherapy and ICB.

Alternate JournalGenome Med
PubMed ID31221199
PubMed Central IDPMC6587285
Grant ListR01 CA198533 / CA / NCI NIH HHS / United States
R01 CA201246 / CA / NCI NIH HHS / United States
R01CA201246 / CA / NCI NIH HHS / United States