Abstract PS2-10-30: Tumor-associated macrophage (TAMs) and cancer-associated fibroblasts (CAFs) profiles in invasive lobular carcinoma (ILC) vs no special type (NST)

Abstract Background: ILC exhibits unique tumor microenvironment (TME) characteristics with abundant stroma and immune evasion. TAMs and CAFs are critical non-lymphoid TME components modulating immune response and progression. We aimed to compare macrophage polarization and CAF subtypes in ILC vs NST (previously known as invasive ductal carcinoma or IDC) using cellular deconvolution platform to generate large-scale transcriptomic data, and to correlate these profiles with immunotherapeutic targets, identifying potential mechanisms of immune evasion and therapeutic opportunities. Methods: 617 breast cancer samples were reviewed by central pathologist for confirmation of histologic diagnosis of ILC or NST. Based on transcriptomic results, they were subsequently classified as histomolecular ILC (hmILC) based on CDH1 inactivation/low expression; or histomolecular NST (hmNST). We analyzed bulk RNA-seq from 126 hmILC (105 Luminal, 21 non-Luminal) and 491 hmNST tumors (274 Luminal, 217 non-Luminal). The Cancer Genome Atlas (TCGA) cohort served as independent validation set. TME composition was determined using Kassandra deconvolution algorithm, quantifying M1/M2 macrophages and CAF subtypes (inflammatory-iCAF, myofibroblastic-myCAF, perivascular-like-PVL). Results: In the discovery set, predicted proportions of macrophage and CAF cell populations were assessed in the experimental cohort across molecularly defined breast cancer groups. Among Luminal hmILC tumors, median proportions were as follows: Macrophages M2 - 0.04, Macrophages M1 - 0.02, iCAF - 0.15, myCAF - 0.07, and PVL - 0.03. In Luminal hmNST tumors, values were comparable: Macrophages M2 - 0.05, Macrophages M1 - 0.03, iCAF - 0.14, myCAF - 0.06, and PVL - 0.02. In the non-Luminal subset, hmILC showed Macrophages M2 and M1 proportions of 0.05 and 0.03, respectively, with iCAF - 0.10, myCAF - 0.03, and PVL - 0.04, whereas hmNST displayed values of 0.05 (Macrophages M2), 0.03 (Macrophages M1), 0.13 (iCAF), 0.05 (myCAF), and 0.02 (PVL). The TCGA validation set showed similar trends to the discovery set; the only statistically significant observation across both cohorts was a modest enrichment of PVL cells in Luminal hmILC compared to Luminal hmNST tumors (p < 0.05, U-test). Conclusions: This large-scale comparative analysis reveals that hmILC harbors an immunosuppressive, stromal-rich TME similar to that of hmNST, characterized by TAM accumulation and FAP^+ myCAF dominance and an equal distribution of M1/M2-polarization ratio. These findings suggest that multiple immune evasion mechanisms are present in ILC, including TAM-mediated suppression. CAF-driven barriers in ILC may contribute to poor immune cell penetration, warranting investigation into CAF-driven modulation and drug delivery. Citation Format: J. Mouabbi, P. pohlmann, B. Lim, R. A. Mukhtar, D. Grachev, B. Baranov, C. Chalabyan, D. Goncharova, P. Turova, K. Chernyshov, V. Kushnarev, F. Paradiso, J. Litton, R. Layman, F. Meric-Bernstam, J. Rodon. Tumor-associated macrophage (TAMs) and cancer-associated fibroblasts (CAFs) profiles in invasive lobular carcinoma (ILC) vs no special type (NST) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-10-30.