Abstract A052: Dissecting the immune regulatory mechanisms of distinct PI3K alterations in invasive lobular carcinoma
Authors: Antoinette van Weverwijk, Michael Schubert, Joseph Siefert, Martine van Miltenburg, Kim Vrijland, Julia Houthuijzen, Anne Stunnenberg, Cheei-Sing Hau, Lodewyk Wessels, Jos Jonkers, Karin E de Visser
Journal: Cancer Research (2024)

Abstract Immunotherapy has been far less effective in breast cancer compared to other cancer types, with only a small fraction of patients having clinical benefit. Historically, invasive lobular carcinomas (ILC), the second most common histological subtype of breast cancer, have been categorized as immunological cold tumors, but recent studies suggest that ILCs may recruit a myeloid-rich immunosuppressive immune landscape. Cancer cell intrinsic features such as the genetic makeup of tumor cells can dictate the spatial distribution, composition and activation state of immune cells, which can exert both anti-tumor and pro-tumor activities and affect disease progression and immunotherapy response. Genetic aberration in key genes of the phosphoinositide-3 kinase (PI3K) signaling pathway are observed in &amp;gt;50% of primary ILCs. The overall aim of this project is to determine whether genetic aberrations in key genes of the PI3K pathway regulate the composition and functional state of the immune landscape, and whether this influences the clinical benefit of immunomodulatory strategies in ILC patients. To dissect the immune regulatory mechanisms of distinct PI3K alterations we have used transgenic ILC mouse models, in which immune profiling studies by flow cytometry and immunohistochemistry revealed that distinct PI3K alterations in cancer cells differentially affect the tumor immune landscape. With some mutations driving a myeloid-rich tumor microenvironment, whereas the immune landscape of tumors harboring other PI3K mutations is dominated by lymphoid cells. To understand the observed cancer genotype-immunophenotypes mechanistically, we have performed single-cell RNA sequencing and secretome analysis to assess cellular communication between the cancer cells and the immune system. We identified key differences in ligand-receptor interactions and secreted signaling that can explain the influx of different immunosuppressive immune cell types in the tumor microenvironment of murine ILCs. We are currently investigating whether therapeutic targeting of immunosuppression is a feasible strategy for PI3K-altered ILC tumors with a tumor-promoting immune landscape. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumor microenvironment will provide a greater understanding of interpatient heterogeneity, and will pave the way for the development of novel and more tailored immunomodulatory strategies for ILC patients. Citation Format: Antoinette van Weverwijk, Michael Schubert, Joseph Siefert, Martine van Miltenburg, Kim Vrijland, Julia Houthuijzen, Anne Stunnenberg, Cheei-Sing Hau, Lodewyk Wessels, Jos Jonkers, Karin E de Visser. Dissecting the immune regulatory mechanisms of distinct PI3K alterations in invasive lobular carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A052.