Abstract 106: Selective elimination of CD169+ macrophages in lymph nodes invaded by breast cancers

Abstract

Abstract Background: Lymph node metastasis is known as one of the strongest prognostic factors in breast cancer. The invasion mechanism of metastasized cancer cells in such immune cell-rich organs remains clear. Here, we aimed to elucidate the impact of metastasized cancer cells on the lymph node immune cell landscape. Methods: Multiscale transcriptomic analyses were performed on both metastatic and nonmetastatic lymph node samples from breast cancer patients with lymph node metastasis. As cancer cells interact with lymphocytes in lymph nodes in direct, proximal, and distant manners, we tried to capture the direct and proximal impact on immune cells in invaded lymph nodes by comparing paired metastatic and non-metastatic lymph node samples. Laser-micro-dissected sections were obtained from 17 lymph nodes across six breast cancer patients at stages II‒III, with each patient contributing both types of lymph nodes for direct comparison. We performed bulk transcriptome, spatial transcriptome, and imaging mass cytometry to analyze the obtained lymph nodes. Furthermore, we conducted immunohistochemistry analyses against a larger patient cohort (574 lymph nodes from 58 patients). Results: Comparing the transcriptomes of paired lymph nodes with and without metastasis from the same patients revealed selective downregulation of CD169+ macrophage-related genes in metastatic lymph nodes. The spatial transcriptome indicated a potential depletion of CD169+macrophages, initiators of anticancer immunity, from their residence in metastatic lymph nodes, while other principal immune cell types were unaltered. Mass cytometry imaging revealed that the numbers of CD169+ macrophages were smaller in the metastatic lymph nodes than in the nonmetastatic lymph nodes. Conversely, the number of B cells, CD4+ T cells, CD8+T cells, Treg cells, and CD11c+ cells remained comparable in both lymph node types. Additional immunohistochemistry analysis of 315 nonmetastatic lymph nodes and 159 metastatic lymph nodes from 58 patients with breast cancer showed that a reduced CD169+ macrophage population was prevalent in all breast cancer subtypes. CD169+ macrophages gradually decreased in correlation with pathological lymph node metastasis status, while no correlation was identified with pathological tumor size classification or metastasized cancer volume in invaded lymph nodes. Discussion: CD169+ macrophages are a unique type of resident macrophages in the lymphoid organs that present cancer-derived antigens to CD8+ T cells. The antigen-presenting role of CD169+ macrophages to T cells is a pivotal step in adaptive immunity. The elimination of CD169+ macrophage implies the disruption of the first step of the initial immune response. This study uncovered CD169+ macrophage suppression as a pronounced pathological phenotype in lymph nodes with breast cancer metastasis, thereby establishing it as a critical future therapeutic target. Citation Format: Yurina Maeshima, Tatsuki R. Kataoka, Alexis Vandenbon, Masahiro Hirata, Yasuhide Takeuchi, Yutaka Suzuki, Yukiko Fukui, Yumiko Ibi, Hironori Haga, Satoshi Morita, Masakazu Toi, Shinpei Kawaoka, Kosuke Kawaguchi. Selective elimination of CD169+ macrophages in lymph nodes invaded by breast cancers [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 106.