Rewire the lymph node niche to instruct T cell immunity

Introduction

Lymph nodes (LN) are communication centers within the lymphatic network that instruct T cell priming and differentiation in homeostasis and disease. Multiple layers of control are achieved by a complex network of signals from stromal and immune cell compartments. As a result, spatially segregated LN niches coexist that foster diverse T cell lineages.

T Cell Differentiation in Cancer

In the context of cancer, T cell differentiation is pushed towards the lineage of exhaustion, with a progenitor exhausted T cell population arising in the LN. Hence, LN are central anatomic sites where T cell exhaustion can be controlled and reversed to eliminate cancer. The key question of REWIRE is: What microenvironmental factors determine the differentiation and maintenance of progenitor exhausted T cells in the LN?

Premetastatic Niche Formation

Tumor-derived signals reprogram stromal and immune cells within tumor-draining LN. Thus, a premetastatic niche is formed that supports future metastatic seeding while establishing an immunosuppressive microenvironment. I hypothesize that signals guiding T cell differentiation are altered by premetastatic remodeling of the LN niche, resulting in the generation of exhausted T cells.

Project Objectives

In this project, I aim to:

1. Decode spatial determinants of the progenitor exhausted T cell niche.
2. Manipulate the tumor-draining LN ecosystem to control T cell immunity.

The overarching goal is to dissect how tissue architecture directs molecular responses within the LN niche to regulate T cell exhaustion.

Methodology

We will use high-dimensional imaging technologies to chart the spatial context of progenitor exhausted T cells following tumor progression, as well as a novel myeloid cell-based in vivo delivery platform to specifically target tumor-draining LN.

Expected Outcomes

REWIRE will uncover basic mechanisms of communication between the LN microenvironment and differentiating T cells in the LN, as well as explore the novel concept of controlling T cell responses via manipulating key features of the LN niche.