# Specificity and function of memory-phenotype CD8+ T cells in the tumor environment

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2020 · $50,520

## Abstract

PROJECT SUMMARY/ ABSTRACT
Classically, memory T cells arise after a productive immune response to a foreign pathogen in the periphery,
and are poised to respond more rapidly to repeated pathogen challenge. However, in mice that have never
encountered foreign pathogens, there is a major subset of endogenous CD8+ T cells that express phenotypic
markers of immunological memory, making up 10-20% of total peripheral CD8+ T cells. Despite the prevalence
of this “memory phenotype” CD8+ T cell (CD8-MP) population, the nature of the antigens recognized by these
cells and the anatomical sites in which they develop remain incompletely defined. Previous work has been
limited to the study of bulk polyclonal CD8-MP cell populations, which may exhibit phenotypic and functional
heterogeneity. This proposal seeks to elucidate fundamental aspects of the biology of CD8-MP cells at the
clonal level. Using a unique clonal approach, this work seeks to elucidate the origin, antigen specificity, and
function of CD8-MP cells at steady state and in the context of oncogene-driven prostate tumors. The central
hypothesis of this proposal is that TCR recognition of endogenous self-ligands in the periphery drives the
differentiation of CD8-MP clones, as well as the selective recruitment of these clonotypes into murine prostate
tumors. The studies in Aim 1 will determine the extent to which CD8-MP differentiation is driven by TCR
recognition of endogenous self-ligands and to elucidate whether CD8-MP differentiation occurs in the thymus
or in the periphery. These studies are expected to demonstrate that a large fraction of CD8-MP cells express
TCRs that recognize self-ligands presented by classical MHC class-I molecules in the periphery, which drives
their differentiation into the CD8-MP subset. The studies in Aim 2 will define the contribution of CD8-MP cells
to the pool of tumor-infiltrating lymphocytes and determine the functional impact of CD8-MP cells on TRAMP
prostate tumors. It is anticipated that CD8-MP clonotypes make up a substantial fraction of prostate tumor-
infiltrating CD8+ T cells, suggesting that CD8-MP T cells reactive to non-mutated self-ligands may play a
unique functional role in the tumor environment. Such evidence would help explain a long-standing conundrum
in tumor immunology, in which T cells reactive to tumor-expressed neo-antigens, differentiation antigens, or
cancer testis antigens can be detected in primary human tumors but are typically rare, indicating that the
majority of tumor-infiltrating T cells have undefined specificities. Ultimately, understanding the biology of this
prominent subset of CD8+ cells at homeostasis and in the tumor microenvironment will provide unique insight
for future preclinical studies aimed at manipulating autologous CD8-MP cells for therapeutic benefit.

## Key facts

- **NIH application ID:** 9851737
- **Project number:** 5F30CA236061-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Christine Miller
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851737

## Citation

> US National Institutes of Health, RePORTER application 9851737, Specificity and function of memory-phenotype CD8+ T cells in the tumor environment (5F30CA236061-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851737. Licensed CC0.

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