# Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $536,024

## Abstract

Project Summary
Anti-PD-1 therapy reinvigorates exhausted CD8 T cells, which can lead to complete tumor eradication as early
as 3 weeks. Yet, despite robust T cell reinvigoration in >78% of patients, less than 40% are cured. The goal of
this proposal is to understand why robust reinvigoration of exhausted CD8 T cells by αPD-1 therapy does not
necessarily translate to clinical efficacy.
Exhausted CD8 T cells (TEX) are a major cell type responding to PD-1 blockade. We and others have shown
that αPD-1 therapy (αPD-1) reinvigorates exhausted CD8 T cells, as defined by enhanced proliferation and
cytokine production. TEX are heterogeneous with progenitor and terminally differentiated TEX that have different
roles in anti-tumor immune responses. Progenitor TEX (ProgEX) replenish terminally differentiated TEX (TermEX),
which in turn provide anti-tumor activity. Thus, similar to stem cells, ProgEX represent a reservoir for CD8 T cell
responses against the tumor. Importantly, it is the ProgEX, rather than TermEX, that respond to αPD-1 and
almost exclusively contribute to the early burst of CD8 T cell reinvigoration. Reinvigoration of TEX results in
accelerated differentiation of ProgEX to TermEX, resulting in a numerically greater pool of TermEX and improved
tumor control. However, at the same time, the accelerated differentiation induced by αPD-1 places increased
stress on ProgEX homeostasis. This raises the possibility that a ProgEX niche is key for providing the cells and
signals necessary to prevent the depletion of ProgEX, and may prove crucial for the efficacy of PD-1 blockade.
Our central hypothesis is that depletion of ProgEX after αPD-1 impairs clinical efficacy and that a tumor-
associated niche is important in maintaining the pool of ProgEX. In Aim 1, we will test the hypothesis that
αPD-1 results in enhanced differentiation of ProgEX and that that depletion of ProgEX is associated with clinical
progression. We will use combinatorial tetramers and single cell RNA+TCR sequencing to understand how
αPD-1 alters the pool of melanoma-specific ProgEX, and how the size of ProgEX pool in turn, impacts the clinical
efficacy of αPD-1. In Aim 2, we test the hypothesis that tertiary lymphoid structures serve as a tumor-
associated niche for ProgEX, and that increased number or size of ProgEX niches after αPD-1 is associated with
the preservation of ProgEX and clinical efficacy. We will use multiparameter immunofluorescence and spatial
transcriptomics to define the cellular composition of the ProgEX niche, the transcriptional circuits utilized by
ProgEX in the niche, and the importance of the ProgEX niche in preserving the pool of ProgEX.

## Key facts

- **NIH application ID:** 10909191
- **Project number:** 5R01CA273018-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alexander Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,024
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909191

## Citation

> US National Institutes of Health, RePORTER application 10909191, Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy (5R01CA273018-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10909191. Licensed CC0.

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