Cancer cell plasticity and MHC-II–mediated immune tolerance promote breast cancer metastasis to lymph nodes

Abstract

Tumor-draining lymph nodes (TDLNs) are important for tumor antigen–specific T cell generation and effective anticancer immune responses. However, TDLNs are often the primary site of metastasis, causing immune suppression and worse outcomes. Through cross-species single-cell RNA-Seq analysis, we identified features defining cancer cell heterogeneity, plasticity, and immune evasion during breast cancer progression and lymph node metastasis (LNM). A subset of cancer cells in the lymph nodes exhibited elevated MHC class II (MHC-II) gene expression in both mice and humans. MHC-II+ cancer cells lacked costimulatory molecule expression, leading to regulatory T cell (Treg) expansion and fewer CD4+ effector T cells in TDLNs. Genetic knockout of MHC-II reduced LNM and Treg expansion, while overexpression of the MHC-II transactivator, Ciita, worsened LNM and caused excessive Treg expansion. These findings demonstrate that cancer cell MHC-II expression promotes metastasis and immune evasion in TDLNs.

RAB22A as a predictor of exosome secretion in the progression and relapse of multiple myeloma

“…In MM, MDSCs promoted the proliferation of MM cells, and played an immunosuppressive role by inhibiting T cell function and Treg cells amplification [ 42 ]. Treg cells are a subset of T cells with significant immunosuppression, characterized by the expression of Foxp3, CD25 and CD4, which are related to the disease progression and poor prognosis of multiple myeloma [ 43 , 44 ], lung cancer [ 45 ], hepatocellular carcinoma [ 46 ] and breast cancer [ 47 , 48 ]. Treg cells inhibits the immune response of the body, leading to immune escape of tumor cells [ 49 , 50 ].…”

Cancer immunotherapy responses persist after lymph node resection

“…Due to the direct drainage of interstitial fluid from tumor tissue in the lymphatic basin (lymphosome), metastatic dissemination to tumor-draining lymph nodes (TDLNs) occurs in the early stage of cancer growth 19 . Colonization in LNs can block nodal entry of naïve lymphocytes 20 , expand regulatory T cells (Tregs) 21,22 and induce systemic tolerance to favor distant metastasis of cancer cells 22 . LN metastases can also further disseminate to additional metastatic sites 23,24 .…”

Lymph node metastasis: An immunological burden

“…A new study by Lei et al (2023) reveals a dynamic interplay between breast cancer cells and the lymph node (LN) microenvironment that sets up local immune suppression. Interest in the role of LN metastasis is re-emerging along with a shifting clinical landscape where prophylactic LN removal is less common and neoadjuvant immunotherapy shows clinical progress ( Patel et al, 2023 ).…”

“… Lei et al (2023) tested the hypothesis that intratumoral heterogeneity established upon LN invasion directs local immune suppression. Single-cell sequencing of mouse 4T1 primary tumors and their associated LN metastases revealed transcriptional states specific to the LN, including the emergence of mesenchymal-like state and high expression of the major histocompatibility complex II (MHC-II).…”

“…Indeed, when LN burden was low, mesenchymal-like cells predominated. With metastatic outgrowth, however, a spatially segregated epithelial state re-emerged in LNs, which specifically expressed high levels of MHC-II leading to enhanced LN seeding and ultimately poor survival in preclinical models ( Lei et al, 2023 ). Spatially segregated, genomically and transcriptionally distinct tumor cell states are observed across primary and metastatic tumors ( Barkley et al, 2022 ); however, much less is known about the tumor-intrinsic states necessary for LN metastasis and the environmental pressures that induce or maintain them.…”