# Myeloid cell-expressed PTPN22 and anti-tumor immunity

> **NIH NIH F99** · UNIVERSITY OF CHICAGO · 2023 · $47,694

## Abstract

PROJECT SUMMARY
 Immunotherapies that block the checkpoint molecules programmed cell death 1 (PD-1) and its ligand
PD-L1 have revolutionized cancer treatment; however, a significant number of patients display resistance to
immunotherapy, either de novo or with disease relapse after initial response [1-3]. Immunotherapy-refractory
cases have prompted insight into mechanisms of resistance, which should ultimately lead to new strategies to
expand clinical efficacy. Primary resistance is linked to lack of immune cell infiltration within the tumor
microenvironment (TME), an observation which has prompted deeper investigation into the tumor and host
factors that regulate the degree of spontaneous T cell activation and infiltration into tumor sites. One relevant
source of inter-patient heterogeneity is the variable presence of polymorphisms (SNPs) in immune-regulatory
genes, many of which have been linked previously to the propensity towards autoimmunity.
 In the F99 phase of this proposed plan, I will evaluate the utility of targeting an autoimmune-associated
gene to increase immunotherapy efficacy. A SNP in the tyrosine-protein phosphatase non-receptor type 22
(PTPN22) gene is attributed with the greatest risk for autoimmune disease outside mutations in the human
leukocyte antigen locus [4-6]. PTPN22 negatively regulates the activation of multiple immune compartments,
with loss-of-function variants leading to heightened immune cell activation in mice and humans [7-8]. This
increase in immune activity is attributed to the expansion of activated CD8+ T cells, however, work reported to
date have utilized global knockout mice (KO), confounding the specific role of PTPN22 in other cell lineages
relevant for anti-tumor immunity, in particular myeloid cells. We thus developed a PTPN22fl/fl mouse to study its
effect in different immune cell types via conditional KO mouse models. I hypothesize that loss of PTPN22
augments the ability of DCs to activate antigen specific CD8+ T cells through 1) improved priming in the
tdLN or recruitment to and/or survival signaling in the TME and that 2) deletion of PTPN22 in
macrophages also may potentiate anti-tumor immunity.
 In the K00 phase of the proposed plan, I aim to identify novel targets governing anti-tumor immunity and
immunotherapy efficacy by 1) identifying autoimmune related SNPs whose loss of function variants correlate
with increased tumor immune infiltration and 2) characterizing the effect of these targets on tumor progression
and immunotherapy response through functional studies using conditional KO mice. This work holds the potential
to elucidate novel therapeutic targets to potentiate anti-tumor immunity. My ultimate goal is to become a tenure-
track faculty member at a leading academic research institution and conduct NIH funded work contributing to the
field of tumor immunology by elucidating anti-tumor immunity and developing novel immunotherapies.

## Key facts

- **NIH application ID:** 10671679
- **Project number:** 5F99CA274689-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Santiago Acero Bedoya
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 5
- **Project period:** 2022-08-01 → 2024-04-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10671679

## Citation

> US National Institutes of Health, RePORTER application 10671679, Myeloid cell-expressed PTPN22 and anti-tumor immunity (5F99CA274689-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10671679. Licensed CC0.

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