Abstract
Lymph nodes (LNs) are highly organized secondary lymphoid organs, and reflective of immune responses to infection, injuries, or the presence of cancer. Extensive molecular and morphological analyses of immune and stromal features in tumors and LNs of breast cancer patients have revealed novel patterns indicative of disease progression. Within LNs, there are dynamic structures called germinal centers (GCs), that act as the immunological hubs for B cell development and generation of affinity matured memory B and antibody-producing plasma cells. Acting as a bridge between systemic and local immunity, associations are observed between the frequency of GCs within cancer-free LNs, the levels of stromal tumor infiltrating lymphocytes, and cancer progression. Scattered throughout the tumor microenvironment (TME) or aggregated in clusters forming tertiary lymphoid structures (TLS), the occurrence of tumor infiltrating B cells (TIL-Bs) has been linked mostly to superior disease trajectories in solid cancers. Recent TIL-Bs profiling studies have revealed a plethora of different TIL-B populations, their functional roles, and whether they are derived from GC reactions in the LN, and/or locally from GC-like structures within the TME remains to be investigated. However, parallels between the immunogenic nature of LNs as a pre-metastatic niche, TIL-B populations within the TME, and the presence of TLS will help to decipher local and widespread TIL-Bs responses and their influence on cancer progression to the lymphatics. Therapies that enhance TIL-Bs responses in the LN GC and/or in GC-like structures in the TME are thus emerging management strategies for breast and other cancer patients.
Highlights
Lymph nodes (LNs) are secondary lymphoid organs that act as a platform to facilitate antigen dispersal and promote interactions between immune cell subsets
- Exploring the responses of tumor infiltrating B cells (TIL-Bs) at the primary tumor, in peritumoral germinal center-like structures and in lymph nodes will inform the development of novel therapies
Lymphatic involvement is more prevalent in Triple-negative breast cancers (TNBCs) and contributes to both local and distant metastasis (Shen et al, 2014; van Roozendaal et al, 2016; Yao et al, 2019). Both TNBC and human epidermal growth factor receptor 2 (HER2)-positive breast cancers often present with more immune infiltrated tumors compared to other subtypes, and stromal tumor-infiltrating lymphocytes (sTILs) assessment of these breast carcinomas have been shown to be superior to classical TNM staging when predicting outcome and response to anti-HER2 therapy, chemotherapy, and immunotherapy (Salgado et al, 2015; Ignatiadis et al, 2019; Loi et al, 2019, 2020)
Summary
- Deep single-cell profiling has revealed a plethora of markers and new TIL-B populations, and for many their functional role remains to be determined. - Exploring the responses of TIL-Bs at the primary tumor, in peritumoral germinal center-like structures and in lymph nodes will inform the development of novel therapies
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