# Germline Determinants of the Breast Cancer Immune Microenvironment

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $37,997

## Abstract

PROJECT SUMMARY/ABSTRACT
Developing effective therapies to interfere in the tumor immune evasion process is a challenge further
complicated by interindividual variability in tumor-host immunological interactions. Genome-wide association
studies (GWAS) have been instrumental in understanding interindividual variability in the context of disease risk;
however, due to the lack of large databases characterizing tumor immune phenotypes, there is a still a gap in
our knowledge of the dynamics of tumor-host immune interactions. The Carter laboratory has recently
demonstrated the role of genotype at the major histocompatibility complex (MHC) in shaping the landscape of
presented somatic mutations (Marty et al. 2017, Marty et al. 2018). MHC genotypes were found to influence
oncogenic mutation probabilities; driver mutations effectively presented by an individual’s inherited MHC, and
thus subject to immunosurveillance, were less likely to be observed than driver mutations that did not bind the
MHC. The common single nucleotide polymorphism (SNP) rs351855 known to be a marker of poor prognosis in
several cancers generated a novel binding site for STAT3, suppressing cytotoxic CD8+ and promoting
immunosuppressive CD4+FoxP3+CD25+ regulatory T cell infiltration in breast and lung cancer murine models
(Kogan et al. 2013). These published findings define a critical role for germline variation in shaping the tumor
immune microenvironment that is still poorly explored. For this proposal, we reasoned contrasting ER+ and ER-
breast cancer subtypes, which have differences in immune cell infiltration, baseline immunotherapy response
rates, and inflammatory effects, could form the basis for novel germline studies. We plan to use the distinct ER+
and ER- breast cancer immune microenvironments to identify and investigate germline variants that modify
tumor-immune interactions. Towards this hypothesis, I have identified SNPs significantly associated with immune
phenotypes, such as
IFN-¡ expression and cytolytic activity, and with cell-type specific effects. Guided by this
promising preliminary data, I propose two Specific Aims to 1) elucidate immune associations and regulatory
mechanisms of common germline variants differentially associated with ER+ and ER- breast cancer and 2)
integrate common and rare germline single nucleotide variants (SNVs) to predict tumor-immune phenotypes.
These aims will leverage powerful bioinformatic analyses and develop innovative models to disentangle
mechanisms and relevant cell contexts of the variants. Expected outcomes will provide essential insights into
the genomic determinants of immune system-mediated tumor elimination and set up future efforts in precision
onco-immunology related to cancer risk, progression and treatment responses. The proposed interdisciplinary
research will take place at UC San Diego under the guidance of mentors who are experts in cancer genomics,
immunology, and clinical medicine. This proposal will help me receiv...

## Key facts

- **NIH application ID:** 10068663
- **Project number:** 1F30CA247168-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Meghana S. Pagadala
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,997
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068663

## Citation

> US National Institutes of Health, RePORTER application 10068663, Germline Determinants of the Breast Cancer Immune Microenvironment (1F30CA247168-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10068663. Licensed CC0.

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