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

Autor: Lhuillier C; Department of Radiation Oncology, Weill Cornell Medicine, Stich Radiation Oncology Center, 525 East 68th Street, New York, NY, 10065, USA., Rudqvist NP; Department of Radiation Oncology, Weill Cornell Medicine, Stich Radiation Oncology Center, 525 East 68th Street, New York, NY, 10065, USA., Elemento O; Department of Physiology and Biophysics, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.; Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, New York, NY, 10021, USA., Formenti SC; Department of Radiation Oncology, Weill Cornell Medicine, Stich Radiation Oncology Center, 525 East 68th Street, New York, NY, 10065, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA., Demaria S; Department of Radiation Oncology, Weill Cornell Medicine, Stich Radiation Oncology Center, 525 East 68th Street, New York, NY, 10065, USA. szd3005@med.cornell.edu.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. szd3005@med.cornell.edu.; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. szd3005@med.cornell.edu.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2019 Jun 20; Vol. 11 (1), pp. 40. Date of Electronic Publication: 2019 Jun 20.
DOI: 10.1186/s13073-019-0653-7
Abstrakt: 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.
Databáze: MEDLINE
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