Immunotherapeutic targeting of intratumoral MAIT cells through modulation of type-17 and type-1 signaling pathways

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that, when activated, can rapidly produce cytokines associated with both type-17 (IL-17 and IL-22) and type-1 (IFN-γ and TNF) responses.

MAIT cells have recently been shown to be enriched in colorectal cancer (CRC) where they may be biased towards a pro-tumor, type-17 cytokine profile.

Here, we aim to investigate the mechanisms that drive this phenotypic switch and identify potential therapeutic targets that can redirect MAIT cells towards antitumor, type-1 responses in situ.

In year 1, we will combine newly developed MAIT cell culture models with a systematic multi-omics approach to evaluate key signaling pathways associated with MAIT cell phenotype.

In years 2&3, we will demonstrate the therapeutic potential of modulating these pathways by generating CRISPR/Cas9 knockout (k/o) MAIT cells for the genes of interest and screen for functional targets in vitro using activation assays and flow cytometry.

We will also validate the antitumor potential of the k/o MAIT cells in a humanized mouse model engrafted with CRC cells.

The findings from this project will improve our understanding of the extracellular cues and intracellular signaling pathways which mediate intratumoral MAIT cell functions.

Given that T cell homing remains a major obstacle in cancer immunotherapy, the ability to target T cells which are naturally enriched in tumor tissues would represent a significant breakthrough in the field.