# Systems Biology of Antigen and T-Cell Transport in Cancer Immunotherapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $463,816

## Abstract

ABSTRACT
Cancer cells often exploit immune checkpoint molecules to suppress and evade immune responses;
by inhibiting this process, immune checkpoint blockers (ICBs) have transformed cancer treatment.
Unfortunately, ICB therapy only benefits <20% of patients, and there are no robust biomarkers for
predicting response in any individual patient. Recent data confirm that effective ICB responses require
activation of new T cells in lymph nodes. The T cell receptors on a given T cell are specific for certain
antigen epitopes, and only a small subset of naive T cells can recognize tumor antigens. Activation of
naïve T cells to initiate the anti-tumor response requires physical interaction with an antigen presenting
cell (APC) displaying the correct, specific cognate antigen recognized by that specific T cell. The co-
localization of the APC, naïve T-cell and cognate antigen is facilitated by the lymphatic system, which
can concentrate APCs and antigen in lymph nodes. However, due to the rich diversity of antigen
reactivity of the T cell population, there are limited numbers of T cells specific for any single antigen.
This fact, along with the random nature of T cell circulation and sampling of the many lymph nodes,
suggests that T cell activation depends on stochastic processes. Logically, the presence of more
antigen, or antigen in more lymph nodes should increase the probability of T-cell activation.
Furthermore, the trafficking and interaction of naïve T-cells and APCs can be disrupted by the presence
of metastatic cancer cells in the lymph node, which impairs anti-cancer immune responses and the
response to ICB. The proposed work analyzes how lymph node metastases impair the generation of
anti-cancer immune responses. We hypothesize that mechanical and physiological disruptions caused
by metastases can interfere with lymph flow, antigen transport and T cell trafficking in the lymph node,
and therefore directly affect anti-tumor immunity by reducing the probability of lymphocyte activation.
In this project, we will address this hypothesis using mechanistic, multiscale computational modeling to
identify specific reasons for the failure to initiate anti-tumor immunity. Our computational model will be
supported by our unique, state-of-the-art animal models to measure immune cell trafficking, lymphatic
function and tumor growth in various conditions. Once validated, the computational model will provide
a mechanistic framework for selecting additional treatments to increase lymphocyte activation and thus
the response rate to immunotherapy. We have assembled a team of leading computational modelers,
lymphatic biologists, immunologists and cancer biologists. This multidisciplinary team is supported by
expert collaborators in biostatistics, computational models of lymph nodes and measurements of lymph
flow in vivo. Together, the R01 team will gain critical insights into modes of failure of immune checkpoint
blockade and develop testable solutions to unleash...

## Key facts

- **NIH application ID:** 10874773
- **Project number:** 5R01CA284603-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Lance L. Munn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,816
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874773

## Citation

> US National Institutes of Health, RePORTER application 10874773, Systems Biology of Antigen and T-Cell Transport in Cancer Immunotherapy (5R01CA284603-02). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10874773. Licensed CC0.

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