# Immunosuppressive impact of the GPCR/MALT1 protease axis in triple-negative breast cancer > **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $53,974 ## Abstract PROJECT SUMMARY/ABSTRACT Breast cancer is the most common cancer in women. Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER-), progesterone receptor (PR-) and human epidermal growth factor receptor 2 (HER2-), the most common targetable markers in breast cancer. TNBC demonstrates the worst overall prognosis among breast cancer subtypes due to lack of well-established targeted therapies. Because TNBC treatment relies heavily on non-specific therapies, a significant need exists to identify innovative ways to harness the tumor immune microenvironment to enable the effective use of immunotherapy. I propose to investigate how the intracellular protein MALT1 promotes immunosuppression in the tumor immune microenvironment (TIME) in TNBC. MALT1 is the effector protein of the CARMA-BCL10-MALT1 (CBM) signalosome, a protein complex that is stimulated downstream of certain oncogenic G protein-coupled receptors (GPCRs) and induces pro-survival NF-κB transcriptional activation. MALT1 acts via two main biologic functions: (1) as a molecular scaffold and (2) as a protease. Our laboratory has demonstrated that in TNBC cells, MALT1 protease activity promotes tumor progression and metastasis by inducing epithelial-to-mesenchymal transition (EMT). In many cancers, including TNBC, malignant cells undergoing EMT modulate the surrounding microenvironment to polarize immune cells toward a cancer-promoting, immunosuppressive phenotype. Based on my preliminary data, I hypothesize that MALT1 protease activity within TNBC cells promotes tumor immune suppression through production of an immunosuppressive secretome. In Aim 1 of this proposal, I will analyze MALT1 regulation of the TNBC TIME by characterizing MALT1 protease- dependent secretion of immunosuppressive cytokines from TNBC cells. Experimental techniques utilized in this aim will include CRISPR/Cas9 editing, mouse breast cancer models, tumor cell/immune cell co-culture, flow cytometry, single cell RNA sequencing, and Olink® proteomics. In Aim 2 of this proposal, I will evaluate a novel MALT1 protease activity gene signature for its clinicopathologic utility in predicting TIME status in TNBC. Experimental techniques utilized in this aim will include use of patient-derived organoids, analysis of patient tumor specimens, multiplex multispectral immunofluorescence, and a series of in silico analyses. In summary, this project evaluates MALT1 protease as a potential driver of tumor progression via its effects on the TNBC TIME. Completion of this proposal will provide me with rigorous research training by a remarkable team of scientists and physician-scientists. This training experience will prepare me for a career as a physician- scientist who develops new and innovative strategies for the treatment of patients with malignant solid tumors. ## Key facts - **NIH application ID:** 10994892 - **Project number:** 1F30CA294747-01 - **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH - **Principal Investigator:** John Walton Little - **Activity code:** F30 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $53,974 - **Award type:** 1 - **Project period:** 2024-07-01 → 2028-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10994892 ## Citation > US National Institutes of Health, RePORTER application 10994892, Immunosuppressive impact of the GPCR/MALT1 protease axis in triple-negative breast cancer (1F30CA294747-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994892. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*