Potentiating effect of reovirus on immune checkpoint inhibition in microsatellite stable colorectal cancer

Abstract

The majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among KRASMut cells, microarray/computational analysis revealed microsatellite status-oriented activation of immune-response pathways. Reovirus plus anti-PD-1 treatment increased cell death among MSS cells ex vivo. Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, KRASMut], but not in MC38 [microsatellite unstable/MSI, KRASWt] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, we observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion. The current investigation sheds light on the immunological mechanisms of the reovirus-anti-PD-1 combination to reduce the growth of MSS CRC.

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

“…Pelareorep, a proprietary isolate of the reovirus Type 3 Dearing strain, has shown varied efficacy in treating melanoma, glioblastoma, colorectal, lung, and ovarian cancers ( 71 ). Although much of the therapeutic capacity of reoviruses is attributed to their ability to selectively replicate in and lyse RAS-transformed cells, several studies have demonstrated the ability of oncolytic viruses to trigger the host immune system against infected tumor cells, which could augment tumor elimination ( 22 , 26 – 28 ). It was further shown that reovirus anti-tumor activity is mediated through the activation of innate and adaptive host immune systems through dendritic cells, NK cells, and effector T-cells ( 72 , 73 ).…”

“…In addition, reovirus treatment enhanced the memory response of the immune system (25). Altogether, it has been shown that reovirus significantly alters the immune response towards the tumor (22,(25)(26)(27)(28).…”