# Targeting of a Major Immune Evasion Pathway in Triple-negative Breast Cancer

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $475,682

## Abstract

Therapeutic Targeting of a Major Immune Resistance Pathway in Triple-negative Breast Cancer
Abstract
Checkpoint blockade results in moderate survival benefit in a subset of patients with triple-negative breast
cancer (TNBC) but most patients currently fail to benefit from immunotherapy. We recently discovered that the
genes encoding the integrin αV and SOX4 proteins (ITGAV and SOX4 genes) render tumor cells resistant to
killing by cytotoxic T cells. Integrin αVβ6 and SOX4 form a resistance pathway that is particularly relevant to
TNBC: Integrin αVβ6 releases TGFβ from an inactive latent complex by a force-dependent mechanism, and
active TGFβ induces expression of the SOX4 transcription factor that inhibits T cell-mediated tumor immunity.
The integrin αVβ6 heterodimer is expressed at a low level by healthy epithelial cells, but its expression is
highly upregulated in many epithelial cancers, including TNBC. TGFβ is an important immunosuppressive
cytokine in human tumors, but has been difficult to target due to its pleiotropic biology in different cell types and
tissues. This approach provides an opportunity for more selective targeting of TGFβ for cancer
immunotherapy. Our preliminary data demonstrate that an integrin αVβ6 blocking mAb inhibits SOX4
expression and sensitizes TNBC cells to cytotoxic T cells. This antibody confers a substantial survival benefit
in two aggressive mouse models of TNBC that are resistant to checkpoint blockade. In Aim 1, we will study
the integrin αVβ6 – SOX4 resistance pathway as an immunotherapy target in aggressive and highly metastatic
mouse models of TNBC. In particular, we will examine how inhibition of integrin αVβ6 induces a substantial
influx of CD8 T cells into TNBCs that are poorly infiltrated by T cells. In Aim 2, we will investigate the
molecular mechanisms by which the integrin αVβ6 – SOX4 pathway inhibits T cell-mediated tumor immunity.
Preliminary data demonstrate that the SOX4 transcription factor inhibits expression of genes from multiple
innate immune pathways in tumor cells, including the cytosolic dsRNA and dsDNA sensing pathways as well
as the type 1 interferon response pathway. We will define the direct transcriptional targets of SOX4 and study
how SOX4 cooperates with other transcription factors to render tumor cells resistant to T cell-mediated tumor
immunity. In Aim 3, we will study the significance of the integrin αVβ6 – SOX4 pathway in human TNBC. Our
hypothesis is that this resistance pathway inhibits T cell infiltration in human TNBC, and we will therefore
examine the spatial relationship between integrin αVβ6/SOX4 expression and T cell infiltration in human TNBC
specimens. High-affinity integrin αVβ6 antibodies and a small molecule inhibitor are already being tested in
clinical trials for fibrosis indications. The studies described here could thus provide the scientific rationale for
testing of such inhibitors in TNBC and other human cancers of epithelial origin.

## Key facts

- **NIH application ID:** 10400167
- **Project number:** 5R01CA251599-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Kai W Wucherpfennig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,682
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400167

## Citation

> US National Institutes of Health, RePORTER application 10400167, Targeting of a Major Immune Evasion Pathway in Triple-negative Breast Cancer (5R01CA251599-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400167. Licensed CC0.

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