T cell expressed miR-155 promotes antitumor immunity and immune checkpoint blockade responses in colon cancer through repression of Ship1 - PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the second deadliest cancerglobally and has the third-highest incidenceand mortality rate of all cancers in the United States. Patients under 50 years old are increasingly presenting with advanced- stage CRC, which has a five-year survival rate of 14% with the current standard of care. Thus, new treatment options, such as immune checkpoint blockade (ICB), are being explored. T cell inactivation often occurs in tumors, leading to a poor immune response. ICB often induces a robust antitumor immune response by blocking T cell inactivation in patients with microsatellite instability-high (MSI-H) metastatic CRC. This high response rate is due to an immune cell-mediated inflammatory tumor microenvironment (TME) in these patients. However, a majority of CRC patients have an immune-suppressive TME, rendering ICB ineffective. As such, the long-term goal of this project is to understand and to modulate the T cell compartment to improve ICB responses in CRC patients that are typically non-responders to ICB therapy via non-coding RNAs. The objective of the proposal is to convert immune cell-depleted colon tumors into immune cell-enriched ones by manipulating T cell microRNA- 155 (miR-155), a classically proinflammatory microRNA (miRNA), and its targets. The central hypothesis is that T cell microRNA-155 promotes a Th1 and cytotoxic T lymphocyte (CTL)-enriched TME in colon cancer by inhibiting Th2 cell polarization and promoting ICB response. We also hypothesize that Ship1, a canonical miR- 155 target, promotes the proinflammatory TME by increasing IFNγ production fromTh1 cells and CTLs to reduce tumor growth. This hypothesis is based on preliminary data that correlate T cell gene signatures in human CRC with miR-155, which is necessary for antitumor immunity and ICB responses against colon cancer in our mouse models. The rationale for this work is that by altering T cell miRNAs or their downstreamtargets, we can promote inflammatory immune cell infiltration into the colon TME. Subsequently, an ICB response can be elicited in colon cancer patients regardless of MSI status. Based on our preliminary data, the central hypothesis will be tested through two specific aims: 1) determine whether T cell miR-155 inhibits Th2 cell polarization, promoting ICB responses in a mouse model of colon cancer, and 2) determine whether inhibiting SHIP-1, a T cell miR-155 target, promotes antitumor immunity, enhances ICB responses, and restricts tumor growth. This study is innovative as it aims to study MSI-H associated miR- 155 and SHIP-1 expression in the context of T cells, the primary target of ICB therapy. The proposed research is significant because it addresses the need for new therapeutic targets to potentiate ICB responses in non- responsive CRC patients.
