# Functional Activation of Low Affinity TILs

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $406,837

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in understanding how to activate and increase tumoricidal activity low-affinity tumor
infiltrating lymphocytes (TILs) that recognize antigens derived from dysregulated unmutated proteins.
Continued existence of this gap represents an important problem because there are many tumors with a low
mutation load that do not respond to current treatments, but elicit low-affinity T cell responses. Our long-term
goal is to identify unique inhibitory receptors that are functionally enriched in TILs and epigenetic targets to
help establish mechanisms that contribute to development of future therapies for these cancers. The
overarching goal of this research is to elucidate pathways that can be harnessed to improve antitumor T cell
activity, particularly the activity of low-affinity TILs. The central hypothesis is that the antitumor activity of low-
affinity T cells is sensitive to enhancement by blocking inhibitory receptors and targeting epigenetic regulatory
regions. This hypothesis has been formulated on the basis of preliminary data produced in the applicants'
laboratories. The rationale for the proposed research is that understanding the activation and differentiation of
low-affinity T cells has the potential to translate into better understanding of better therapies for cancer that
now afflicts one of every two to three people in this country. Guided by strong preliminary data, this hypothesis
will be tested by pursuing two specific aims: 1) Establish mechanisms that modulate antitumor activity of low-
affinity TILs by defining their inhibitory receptor repertoire, and 2) Establish mechanisms of epigenetic
programming in low-affinity TILs. Both of these aims will use retrogenic technology to generate large pools of
either high or low-affinity tumor-specific T cells. In the first aim, inhibitory receptors will be identified from a list
of ITIM-containing genes that were found by the investigators to be upregulated in TILs and using biochemical
approaches that identifies inhibitory receptors from low-affinity T cells using SH2 domains. The genes of
interest identified in this aim will be confirmed in other systems and probed on human colorectal samples to
determine their expression on human TILs. In the second aim, gene expression and chromatin accessibility of
low and high affinity T cells in the periphery and tumor will be examined. The effects of T cells development in
tumor antigen-deficient mice will also be examined. The approach is innovative, in the applicant's opinion,
because it departs from the status quo of looking at the highest affinity reactions against tumors using novel
methods. The contribution of the proposed research will be significant because identification of inhibitory
receptors and epigenetic targets expected to activate endogenous low-affinity T cells may have fewer toxicities
and activate T cells in some tumors that have not yet experienced the benefits of immunotherapies. Ulti...

## Key facts

- **NIH application ID:** 10297834
- **Project number:** 5R01CA226879-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jill E Slansky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $406,837
- **Award type:** 5
- **Project period:** 2018-12-03 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297834

## Citation

> US National Institutes of Health, RePORTER application 10297834, Functional Activation of Low Affinity TILs (5R01CA226879-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297834. Licensed CC0.

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