# Strategies to predict and overcome resistance to cancer immunotherapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $520,119

## Abstract

Immunotherapies such as PD-1 blockade have revolutionized cancer care. Yet
most patients do not experience sustained (durable) benefit from blockade of T cell
inhibitory receptors. Unfortunately, current biomarkers do not adequately predict patient
response or resistance to immunotherapy; and successful strategies to overcome
immunotherapy resistance have been lacking. Both gaps reflect our incomplete
understanding of how durable immunity carried out by T cells is achieved. Progenitor T
cells normally balance the mutually opposing demands of differentiation and self-
renewal by transmitting unequal anabolic activating signals to daughter cells. In the
setting of cancer, however, sustained T cell activation skews the normal
regenerative equilibrium of balanced differentiation and renewal towards progressive
dysfunction of differentiated cells along with progressive loss of self-renewing T cells. It
was previously presumed that PD-1 blockade acted by restoring potency to the most
dysfunctional T cells. Instead, emerging consensus has demonstrated that PD-1
blockade can only function by inducing greater division and differentiation of self-
renewing T cells, which are already in peril. This preclinical and translational application
marshals our basic discoveries concerning the signaling and cell biology of T cell
regeneration to tackle a major clinical roadblock in cancer care. Performing the aims of
this proposal will enable determination of 1) whether anti-cancer immunity and
immunotherapy impact the self-renewal of CD8+ T cells; 2) whether immunotherapy can
be improved by augmenting CD8+ T cell self-renewal; and 3) whether patient response
and resistance to immune checkpoint blockade can be predicted from the abundance of
self-renewing T cells. This proposal would address two critical unmet patient needs: a
non-invasive predictive biomarker for response and resistance to immunotherapy
across cancer types; and a novel strategy for resistance-directed treatment enabling
immunotherapy to benefit the majority, rather than the minority of patients.

## Key facts

- **NIH application ID:** 10795868
- **Project number:** 5R01CA279268-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** STEVEN L REINER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $520,119
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795868

## Citation

> US National Institutes of Health, RePORTER application 10795868, Strategies to predict and overcome resistance to cancer immunotherapy (5R01CA279268-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10795868. Licensed CC0.

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