Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

Abstract

Abstract Tumor-draining lymph nodes (TDLNs) enlarge and remodel in many human cancer patients and murine tumor models, featuring extensive lymphocyte accumulation, lymphatic sinus growth (lymphangiogenesis), and increased lymph flow. B cells can drive these lymphatic alterations, however the cellular and molecular mechanisms that direct lymphocyte accumulation in TDLNs are unknown. This study investigated whether lymphocyte accumulation in TDLNs is due to increased entry via high endothelial venules. The popliteal lymph node of C57Bl/6 mice bearing unilateral footpad B16-F10 melanoma tumors exhibits an 8-fold increase in B cells and 3-fold increase in T cells. Comparative measurements of labeled-lymphocyte entry into TDLNs versus the contralateral non-tumor draining lymph nodes by flow cytometry only partially explained TDLN hypertrophy. Further investigation of TDLN lymphocyte exit, proliferation, and apoptosis identified distinct mechanisms regulating B and T cell trafficking through TDLNs in response to tumors, including preferential retention of B cells. Surprisingly, B and T cell accumulation in TDLNs occurred without increased lymphocyte activation, suggesting an ineffective anti-tumor immune response. These insights could provide new therapeutic targets to manipulate lymph node lymphocyte content and immune responses to cancer and other diseases.