Abstract 30P
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) is associated with poor prognosis in ILC. So far, the precise impact of E-cadherin inactivation in tumor cells on these stromal peculiarities remains largely unknown. 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.
Methods
To do so, we leveraged a well characterized retrospective series of251 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 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.
Results
By combining these analyses, we found that (1) ILC have more inflammatory CAF and less myofibroblastic CAF than ER+ IBC-NST, (2) this particular feature is dependent on a previously undescribed mechanism involving E-cadherin in CAF plasticity, (3) CAF content in ILC determines the pattern of TIL infiltration and finally, (4) the poor prognostic value of TIL in ILC could be partially related to an immune escape mechanism linked to E-cadherin inactivation in tumor cells.
Conclusions
In conclusion, our results provide strong arguments supporting our hypothesis that E-cadherin inactivation shapes tumor microenvironment specificities in ILC.
Legal entity responsible for the study
The authors.
Funding
AVS received Ruban Rose Grant (Estee Lauder companies) in 2012, which helped fund RNAseq sequencing of ILC samples.
Disclosure
F.C. Bidard: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Rain Oncology; Financial Interests, Personal, Advisory Board: Pfizer, Lilly, Novartis, AstraZeneca, Sanofi, Rain Oncology, GE Healthcare, SAGA Diagnostics, Caris, Daiichi Sankyo, Gilead; Financial Interests, Institutional, Invited Speaker: Pfizer, Sanofi; Financial Interests, Personal, Expert Testimony: Inatherys; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Prolynx, Saga Diagnostics, Seagen, Merck KGaA; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Lilly. A. Vincent-Salomon: Financial Interests, Personal and Institutional, Funding: daichi-Sankyo, AstraZeneca, MSD Avenir, Ibex Medical Analytics, Owkin, Primaa. F. Mechta-Grigoriou: Financial Interests, Institutional, Research Grant, Funding for research: Institut Roche; Financial Interests, Institutional, Research Grant, Funding for developing a clinical trial: Roche. All other authors have declared no conflicts of interest.