Abstract 206: Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity

Abstract

Abstract Background- Triple-negative breast cancer (TNBC) is challenging to treat due to fewer clinically detectable targets and its propensity to metastasize. Epithelial to mesenchymal transition (EMT) is a key feature of the metastatic cascade. Recent data highlights the enhanced metastatic potential of hybrid epithelial-mesenchymal (EM) phenotypes from partial activation of EMT. However, mechanistic insights and targetable vulnerabilities within hybrid EM remain elusive. We identified that hybrid EM tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies. Hence, we sought to investigate role of CD38 in hybrid EM-driven metastasis. We hypothesize that hybrid EM tumors drive metastasis via intratumoral accumulation of CD38, promoting an immunosuppressive tumor microenvironment (TME). Methods- Reverse Phase Protein Array, cell migration/invasion assays, flowcytometry and immunohistochemistry were used to evaluate phenotype, immune cell populations and molecular mechanisms upon CD38 knockdown (KD) and overexpression (OE) in vivo. Results- CD38 KD weakened the process of EMT and reduced cell migration and invasion. Tumors lacking CD38 showed increased infiltration of CD8 T cells and M1-like (anti-tumor) macrophages coupled with a decrease in immunosuppressive regulatory T cells (Tregs) and M2-like (pro-tumor) macrophages. In contrast, cancer cells with CD38 OE maintained a hybrid phenotype through co-expression of epithelial and mesenchymal markers and also showed significant increase in cell migration and invasion. Tumors arising from CD38 OE cells displayed a significant increase in Tregs. Most strikingly, hybrid EM tumors that no longer express CD38 show reduction in lung metastases and circulating tumor cell colonies. Taken together, these findings suggest that CD38 is important for the metastatic and immune evasive potential of hybrid EM breast cancers. Conclusion- Our data exposes CD38 as a survival strategy in hybrid EM tumors to suppress immune cells and sustain metastasis with strong implications in other carcinomas which have hybrid EM properties. Citation Format: Tanvi Visal. Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 206.