Immune Checkpoint Blockade Augments Changes Within Oncolytic Virus-induced Cancer MHC-I Peptidome, Creating Novel Antitumor CD8 T Cell Reactivities

Youra Kim,Prathyusha Konda,J Patrick Murphy,Joao A Paulo,Steven P Gygi,Shashi Gujar

doi:10.1016/j.mcpro.2021.100182

Abstract

The combination cancer immunotherapies with oncolytic virus (OV) and immune checkpoint blockade (ICB) reinstate otherwise dysfunctional antitumor CD8 T cell responses. One major mechanism that aids such reinstatement of antitumor CD8 T cells involves the availability of new class I major histocompatibility complex (MHC-I)-bound tumor epitopes following therapeutic intervention. Thus, therapy-induced changes within the MHC-I peptidome hold the key to understanding the clinical implications for therapy-reinstated CD8 T cell responses. Here, using mass spectrometry–based immuno-affinity methods and tumor-bearing animals treated with OV and ICB (alone or in combination), we captured the therapy-induced alterations within the tumor MHC-I peptidome, which were then tested for their CD8 T cell response-stimulating activity. We found that the oncolytic reovirus monotherapy drives up- as well as downexpression of tumor MHC-I peptides in a cancer type and oncolysis susceptibility dependent manner. Interestingly, the combination of reovirus + ICB results in higher numbers of differentially expressed MHC-I-associated peptides (DEMHCPs) relative to either monotherapies. Most importantly, OV+ICB-driven DEMHCPs contain biologically active epitopes that stimulate interferon-gamma responses in cognate CD8 T cells, which may mediate clinically desired antitumor attack and cancer immunoediting. These findings highlight that the therapy-induced changes to the MHC-I peptidome contribute toward the reinstated antitumor CD8 T cell attack established following OV + ICB combination cancer immunotherapy.

Highlights

In Brief Immune checkpoint blockade augments changes within oncolytic virus-induced cancer major histocompatibility complex (MHC)-I peptidome and contributes toward the therapyinduced novel antitumor CD8 T cell reactivities
Unlike ID8 cancer cells, which express low basal levels of major histocompatibility complex (MHC-I) molecules that are upregulated in response to reovirus infection (Fig. 1A), MCA205 cancer cells express constitutively high levels of MHC-I molecules that remain unaffected by reovirus infection (Fig. 1B)
We reasoned that MCA205 provides a good model to examine reovirusmediated changes to the MHC-I peptidome without the need to account for changes to the MHC-I expression as a possible confounding variable

Summary

Graphical Abstract

In Brief Immune checkpoint blockade augments changes within oncolytic virus-induced cancer MHC-I peptidome and contributes toward the therapyinduced novel antitumor CD8 T cell reactivities. MHC-I Peptidome of Reovirus and ICB Therapy cells, via a localized release of cytokines in the TME [15,16,17] This tumor immune infiltration-driving action of OVs makes them a suitable candidate for making tumors “hot” and supports their use in combination with ICBs. Interestingly, the biological activities of OV monotherapy-induced antitumor CD8 T cell responses are dampened via the actions of immune checkpoints such as PD-1 and require rescuing via ICB to sustain their antitumor functions. The addition of ICB to reovirus therapy showed potential therapeutic value since a greater change to the MHC-I peptidome was observed due to the combination therapy compared with either monotherapy alone These DEMHCPs were capable of inducing antigen-specific CD8 T cell responses in reovirus + ICB-treated tumor-bearing (TB) mice, but not in nontreated TB mice. Such therapy-induced changes within the MHC-I peptidome and inherent changes in CD8 T cell activity may improve antitumor immunity and hold biological as well as therapeutic importance [33]

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION