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

Claire Lhuillier,Olivier Elemento,Nils-Petter Rudqvist,Silvia C Formenti,Sandra Demaria

doi:10.1186/s13073-019-0653-7

Claire Lhuillier, Olivier Elemento + Show 3 more

Open Access

https://doi.org/10.1186/s13073-019-0653-7

Copy DOI

Journal: Genome medicine	Publication Date: Jun 20, 2019
Citations: 180	License type: open-access

Affiliation: Cornell University, Lander Institute

Abstract

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.

Highlights

T cells can recognize differentiation antigens and other non-mutated self-antigens that are overexpressed by cancer cells in the context of sufficient inflammatory signals, which result from the release of damage-associated molecular pattern (DAMP) molecules [1, 2]
We extend the discussion to consider the role of the MHC class II (MHC-II) pathway in presenting the cancer mutanome to CD4 T cells, and we describe additional types of tumor neoantigens that are emerging as targets of antitumor T cells, such as antigens generated by posttranslational modifications (PTMs)
A large set of IFN-stimulated genes was upregulated in cancer cells treated with 8GyX3 but not in those treated with 20GyX1. These findings suggest that the proteome presented by major histocompatibility complex class I (MHC-I) on cancer cells, and on the cross-presenting Dendritic cell (DC) that take up the tumor antigens after radiation exposure, may vary significantly depending on the dose per fraction of radiation applied

Summary

Introduction

T cells can recognize differentiation antigens and other non-mutated self-antigens that are overexpressed by cancer cells in the context of sufficient inflammatory signals, which result from the release of damage-associated molecular pattern (DAMP) molecules [1, 2]. Increased tumor mutational load theoretically leads to the accumulation of neoantigens, only a subset of mutated peptides are presented on MHC-I molecules, and among them, only a small percentage generate T-cell responses.

Results

Conclusion