Decoding Requirements for Infiltration of T ceLLs into solid tumors

Introduction

Cancer immunotherapies that leverage T cell activities are transforming cancer treatment. Currently, enormous effort has been devoted to empowering T cells to recognize and attack tumor cells. In contrast, the trafficking of T cells into tumors, a crucial prerequisite and limiting factor for effective T cell–tumor cell interactions, receives relatively less attention while at the same time being poorly understood. This is due to the complex and dynamic nature of T cell trafficking and the lack of model systems that allow function-based systematic investigation of the specific process.

Project Overview

This proposal integrates innovative functional genomics into physiologically relevant models that recapitulate two essential steps in the migration of effector T cells into tumors to investigate:

1. Chemokine production in the tumor microenvironment (TME)
2. Chemotactic infiltration of T cells into tumors

Here we focus on one of the most devastating cancers, pancreatic ductal adenocarcinoma (PDAC), because it poses considerable physical and biochemical barriers that restrict the access of effector T cells to tumor cells and substantially resists all available therapies.

Research Objectives

We will:

1. Elucidate the (co)regulatory mechanisms of the expression of chemokines that direct T cell recruitment and exclusion.
2. Develop model systems to systematically reveal cell-intrinsic determinants in T cells that influence their capability to infiltrate tumors.
3. Evaluate whether pharmacological or genetic targeting of the modulators of T cell trafficking improves T cell-based cancer immunotherapies.

Expected Outcomes

Collectively, this project will deliver fundamental insight into the mechanisms that regulate T cell trafficking into tumors and may yield novel strategies to broaden or increase the efficacy of the current cancer immunotherapies.