Project 1: Overcoming Immune Exclusion in Microsatellite Stable Colorectal Cancer

PROJECT SUMMARY/ABSTRACT: Project 1 Although immune checkpoint inhibitors (ICIs) are highly effective in microsatellite unstable (MSI-H) colorectal cancer (CRC), it has a limited clinical benefit for the 85% of CRCs that are classified as microsatellite stable (MSS). This is due, at least in part, to a paucity of CD8+ T cells present in these tumors, which we define as immune exclusion (IEX). The aim of Project 1 is to overcome IEX in MSS CRC; we define IEX as a paucity of intratumoral CD8+ T cells. We recently discovered a four-gene signature associated with IEX and worse progression-free survival in MSS CRC. We also discovered that two of the protein products of that signature, DDR1 and TGFBi, are present in supermeres, a secreted amembranous nanoparticle we recently identified. Levels of DDR1 and TGFBi are markedly increased in plasma-derived supermeres of CRC patients. In triple- negative breast cancer, the shed ectodomain of DDR1, a collagen-activated receptor tyrosine kinase, binds to the extracellular matrix so that CD8+ T cells are excluded from the tumor, and these T cells gain entry into the tumor following administration of a neutralizing antibody to DDR1. Project 1 is participating in a clinical trial introducing this neutralizing antibody to DDR1 (PRTH-101) along with the ICI pembrolizumab (Pembro). The premise is that PRTH-101 will allow CD8 T cells to enter the tumor proper, and Pembro will overcome an immune checkpoint to unleash the anti-tumor cytotoxic activity of these CD8+ T cells. Additional goals of this project are to refine the IEX signature to determine markers of non-responsiveness to ICB therapy in MSI-H, as well as to explore the diagnostic and therapeutic implication of DDR1 and TGFBi in supermeres.