Abstract PS18-02: E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

Abstract Background: Invasive lobular carcinoma (ILC) shows distinct clinicopathological features compared to invasive breast carcinoma of no special type (IBC-NST), including specific stromal characteristics. One of them concerns the singular infiltration pattern of lobular tumor cells, which induces minimal stromal reaction. In addition, a key function of tumor microenvironment has been previously demonstrated reporting that tumor-infiltrating lymphocytes (TIL) are not associated with good prognosis in ILC, in contrast to IBC-NST. So far, the precise impact of E-cadherin inactivation in tumor cells on these stromal peculiarities remains largely unknown. Materials and Methods: In this context, we performed an in-depth characterization of heterogeneity, function, and interactions of Cancer-Associated Fibroblasts (CAF) with both immune and tumor cells in ILC compared to IBC-NST. To do so, we leveraged a well characterized retrospective series of 251 patients, who underwent surgery at Institut Curie for a primary ILC between 2005 and 2008, for whom frozen tumor samples were available for RNA sequencing. We established tissue microarrays (TMA) for 158 ER+ ILC from this cohort and 77 primary ER+ IBC-NST from our institute. Based on the TMA cohort, we did comparative immunohistochemical analysis of specific markers of different CAF populations, in particular FAP+ CAF, and immune cells. In addition, we characterized six classical ILC by single cell RNA sequencing and we performed spatial transcriptomic analysis of 16 ILC from the retrospective series. Finally, we studied the interactions of ER+ breast cancer cell lines with CAFs and CD8 T lymphocytes in vitro, using co-culture experiments and selective inactivation of E-cadherin (in tumor cells) or some of its heterologous receptors (especially in CAFs). Results: By combining these analyses, we found that (1) CAF content of ILC is heterogeneous, notably depending on two tumor histopathological features (ILC histological type and tumor cellularity), (2) ILC have more inflammatory CAF and less myofibroblastic CAF than ER+ IBC-NST, (3) this particular feature is dependent on a previously undescribed mechanism involving E-cadherin in CAF plasticity, (4) CAF content in ILC determines the pattern of TIL infiltration which in turn has an independent prognostic impact in this cancer and finally, (5) the lack of good prognostic value of TIL in ILC may be partly explained by a cytotoxic CD8 T cell-related immune escape mechanism associated with E-cadherin inactivation in tumor cells. Conclusion: In conclusion, we have demonstrated for the first time that E-cadherin has a direct effect on CAF differentiation via a previously undescribed mechanism, explaining some of the morphological specificities of the ILC stroma. Furthermore, inactivation of E-cadherin determines both the spatial organization pattern of TILs and the escape of tumour cells from CD8 T cell cytotoxicity. Our data provide an unprecedented insight into the ILC stroma and E-cadherin-mediated modulation of breast cancer tumour microenvironment. Citation Format: Lounes Djerroudi, R. Mhaidly, H. Croizer, G. Gentric, A. Meng, L. Fuhrmann, M. Caly, C.Benoist, V. Renault1, F.C. Bidard3, Y. Kieffer2, A. Vincent-Salomon and F. Mechta-Grigoriou. cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS18-02.