# Targeting antigen presentation to improve immunotherapy responses in breast cancer

> **NIH NIH P50** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $383,600

## Abstract

PROJECT SUMMARY/ABSTRACT: TARGETING ANTIGEN PRESENTATION TO IMPROVE
IMMUNOTHERAPY RESPONSES IN BREAST CANCER
Cancer immunotherapies, particularly those targeting the PD-1/L1 axis, are revolutionizing treatment paradigms.
Although these therapies have proven effective in a wide variety of solid tumors, response rates to single agent
anti-PD-1/L1 in breast cancer have been underwhelming, centering around 5%-15% of treated patients.
However, given the durable responses observed in other tumor types, finding ways to increase breast cancer
sensitivity to immunotherapy is a valuable endeavor. Our recent work in breast cancer and melanoma has
identified an important role for major histocompatibility complex-II (MHC-II) expression on tumor cells as a
mediator of enhanced anti-tumor immunity and subsequent response to immunotherapies targeting the PD-
1/PD-L1 axis. Furthermore, our preliminary studies suggest that both MHC-I and MHC-II expression (antigen-
presenting molecules) on breast tumor cells directly influences the tumor microenvironment through expanded
anti-tumor immunity. We found that activation of the Ras/MAPK pathway suppresses the expression of both
MHC-I and MHC-II, and therefore may be an actionable target for enhancing antigen presentation to promote
anti-tumor immunity and potentiate immunotherapy responses. Based on these data, we have initiated trials in
both metastatic triple-negative breast cancer (TNBC) and ER+ breast cancer testing the efficacy of this
combination. In this proposal, we will perform clinical validation of the molecular effects of MEK inhibition with
anti-PD-L1 in ongoing clinical trials at our institution, as well as perform direct translational studies exploring the
immune mechanism behind MEK inhibition that promotes anti-tumor immunity. Our central hypothesis is that
therapeutic modulation of antigen presentation via MEK inhibition will promote immunotherapy response in
breast cancer through enhanced MHC-I and MHC-II responses. The proposed studies will elucidate mechanism,
validate clinical utility and identify new targets for combinations of therapies that promote anti-tumor immunity
through enhancing antigen presentation. Thus, this proposal will use a translational approach to bring rational
combinations of immunotherapy and molecularly targeted agents to breast cancer patients.

## Key facts

- **NIH application ID:** 10226889
- **Project number:** 5P50CA098131-19
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Justin M Balko
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,600
- **Award type:** 5
- **Project period:** 2003-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226889

## Citation

> US National Institutes of Health, RePORTER application 10226889, Targeting antigen presentation to improve immunotherapy responses in breast cancer (5P50CA098131-19). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10226889. Licensed CC0.

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