B cells facilitate immune evasion of metastasizing cancer cells in tumor-draining lymph nodes 2260657

Abstract Introduction Lymphatic colonization correlates with worse prognosis in several cancers, as lymph nodes act as a reservoir of malignant cells, allowing their dissemination to distant organs. More recently, lymph node metastasis was found to promote systemic immunosuppression, further highlighting the need for a better understanding of the mechanisms supporting its formation. How tumor cells can enter the draining lymph node where anti-tumor immunity is primed and overcome immune recognition remains unknown. Methods To address this outstanding question, we developed a mouse model of trackable pancreatic cancer highly metastatic to the draining lymph node in a well-defined timely manner. We used this model to characterize tumor-draining lymph nodes at the time of tumor cell seeding compared to unperturbed lymph nodes by both single cell RNA-sequencing and spatial multiplexed immunofluorescence. Results Unexpectedly, this unbiased comprehensive analysis of pre-metastatic tumor-draining lymph nodes revealed that the most striking changes corresponded to B cells. We thus investigated the contribution of B cells to the metastatic cascade in genetic models of several B cell deficiencies and antibody-mediated depletion. We observed that metastatic pancreatic cancer cells fail to successfully colonize tumor-draining lymph nodes in the absence of B cells. Interestingly, this phenotype was not specific to our pancreatic cancer model as similar findings replicated in metastatic melanoma. We found that immunosurveillance by T cells is impaired in tumor-draining lymph nodes in the presence of B cells. Additionally, B cells support metastasis through antigen presentation on MHCII. Conclusion Collectively, these data revealed that B cells are required for metastasis formation as they facilitate immune evasion of disseminated cancer cells in the tumor-draining lymph node where anti-tumor T cell immunity is orchestrated. Funding Source Landry Cancer Biology Consortium (Harvard Medical School) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)