# T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $57,464

## Abstract

PROJECT SUMMARY
Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to
achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor
programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a
subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we
need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project
is to understand the role of T cell–intrinsic factors that contribute to patient response versus resistance to
PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade
response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up
of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and
downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters
in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic
of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma
antigen-specific T cells from PD-1 blockade–responsive and –resistant patients to determine how TCR affinity
profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of
patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our
third aim we will use a panel of melanoma patient–derived TCRs with varying affinities for the same antigen
for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade.
Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade
resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for
combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR
affinity profiles.

## Key facts

- **NIH application ID:** 10380381
- **Project number:** 3R01CA243486-02S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MICHELLE KROGSGAARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $57,464
- **Award type:** 3
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380381

## Citation

> US National Institutes of Health, RePORTER application 10380381, T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade (3R01CA243486-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380381. Licensed CC0.

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