Biotherapeutic implications for oncolytic virus-induced MHC class I ligandomes

Oncolytic viruses (OVs) have emerged as a new class of cancer immunotherapeutics. Apart from their direct cancer-killing activity, OVs promote clinically desired immune attack on cancers from CD8 T cells. This OV-induced CD8 T cell attack on tumors can be further potentiated by immune checkpoint blockade (ICB) agents, and as such, OV+ICB combination therapies are becoming routine in clinical testing. Here, OV-induced, ICB-potentiated CD8 T cells can target existing cancer cells at local and metastatic sites, and maintain protection against possible relapse even after the discontinuation of the therapy. Thus, CD8 T cell response is clinically relevant and can be harnessed to enhance the efficacy of OV+ICB therapies. The harnessing of such CD8 T cell response requires information on the MHC-I ligands [MiLs] that drive their biological activity. Unfortunately, the identification of such MiLs, usually 8-11 amino acids long, has remained technologically challenging. We have addressed this challenge by developing the next-generation of applied immunomics and mass spectrometry-based platforms that now streamline the high-throughput discovery and biological validation of MiLs. Interestingly, OVs induce two types of CD8 T cell responses: antitumor and antiviral- which are defined by Mils arising from tumors (TuMiLs) and the virus (ViMiLs), respectively. These MiLs not only shape the clinically relevant biological features of underlying CD8 T cell responses, but also can be harnessed within novel CD8 T cell repurposing therapeutic strategies to attack cancers. In this context, this project is focused on comprehensively understanding the bio-therapeutic implications for TuMiL- and ViMiL-specific antitumor and antiviral CD8 T cell responses, respectively. Our proof-of-concept multi-disciplinary study promises to identify urgently needed information on establishing effective cancer immunotherapies aimed at promoting better outcomes from cancers in clinics.