# Differentiation and function of intratumoral memory-phenotype CD8+ T cells

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $405,000

## Abstract

ABSTRACT
While considerable evidence demonstrates that CD8+ TILs reactive to mutated or non-mutated tumor antigens
play an important role in anti-tumor immunity, expanding evidence indicates that bona fide tumor-reactive T
cells comprise only a minor fraction of all TILs in many human tumors, indicating that most CD8+ TILs have
undefined specificity. Based on this long-standing question, we examined the hypothesis that a substantial
fraction of TILs may represent CD8+ "memory-phenotype" T cells (CD8-MP cells), a unique population of cells
of unknown antigen specificity that comprise 5-10% of CD8+ T cells in unprimed mice, exhibit common
hallmarks of prior antigen experience, and have the capacity to rapidly expand and produce IFN-γ during an
immune response. In preliminary work, we found that CD8-MP cells make substantial contributions to the
immune infiltrate of oncogene-driven prostate tumors, and express high densities of the PD-1 inhibitory
receptor. Given these unique insights, we embarked on parallel studies aimed at further elucidating the
fundamental biology of CD8-MP cells, using a clonal approach to define the developmental trajectories of
these cells. Our new data reveal that the differentiation of many CD8-MP clones is triggered by recognition of
self-ligands in the thymus via a reproducible, orchestrated process, challenging current thought suggesting that
CD8-MP cells differentiate in the periphery in response to homeostatic signals. In Aim 1, we will define the
function of CD8-MP cells in anti-tumor immunity, testing the hypothesis that self-ligand recognition drives the
early entry of CD8-MP cells into developing tumors, and that CD8-MP cells enhance anti-tumor immunity by
catalyzing broader immune cell infiltration. In addition, we will identify novel markers that can be used to
identify intratumoral CD8-MP cells, thereby enabling the broader study of CD8-MP cells in murine cancer
models and human cancer patients. In Aim 2, we will elucidate the molecular and cellular mechanisms that
direct CD8-MP differentiation, testing the hypothesis that CD8-MP differentiation is a two-step process
triggered by TCR-dependent recognition of self-ligands presented by classical dendritic cells in the thymus. We
will also utilize a unique T cell antigen discovery assay to identify natural self-peptides recognized by CD8-MP
cells, thereby opening new areas of inquiry that were previously inaccessible. Ultimately, defining the function
of intratumoral CD8-MP cells and the blueprints of CD8-MP differentiation in mice is expected to open new
avenues for the study and manipulation of these cells in humans.

## Key facts

- **NIH application ID:** 10071490
- **Project number:** 1R01AI150047-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Peter Aidan Savage
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 1
- **Project period:** 2020-06-17 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071490

## Citation

> US National Institutes of Health, RePORTER application 10071490, Differentiation and function of intratumoral memory-phenotype CD8+ T cells (1R01AI150047-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071490. Licensed CC0.

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