Background Lymph nodes (LNs) are secondary lymphoid organs that surveil tissue fluids and initiate adaptive immunity. Due to the direct drainage of interstitial fluid from tumor tissue through lymphatic vessels to lymph nodes, metastatic dissemination to tumor draining lymph nodes (TDLNs) occurs in early stage of cancer, making LN metastatic burden a strong prognostic factor for patient outcome. LN surgery to prevent metastatic recurrence, including sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND), are commonly performed in the clinic. Intriguingly, ectopically implanted murine tumors, such as MC38 (colon adenocarcinoma) and CT26 (colon carcinoma),1 2 have impaired immune checkpoint blockade (ICB) response after resection of TDLNs. However, in phase III clinic trials, patients with completely resected stage IIB, IIC, III or IV melanoma (primary tumor, sentinel LNs and disease-related LNs all removed) benefited from ICB treatment.3–5 The inconsistence between pre-clinic and clinical findings demands further investigation of how TDLN resection affects ICB efficacy.
Methods Through comparing progression-free survival, recurrence-free survival and hazard ratio reduction among multiple phase III clinical trials (EORTC18071, Checkmate066, Checkmate067, Checkmate238 and Keynote716), relative efficacy of ICB is assessed in melanoma patients with various extent of LN surgery. Breast cancer (E0771) and melanoma (B16F10) murine tumor models are implanted to orthotropic sites to evaluate impacts of TDLN dissection on response to ICB treatment and antigen transport. Computational model is developed to predict lymph flow in patients after LN surgery. The radiology images (at diagnosis and follow-up visit) of head and neck cancer patients treated by neoadjuvant durvalumab and irradiation are used to validate the presence of remaining reactive LNs.
Results LN dissection does not diminish ICB-mediated survival improvement (figures 1,2), despite the important role of TDLNs in anti-tumor responses. Mechanistically, after TDLN resection, antigen can be transported to distal LNs through remodeled lymph drainage, which extends the responsiveness to ICB (figures 3, 4). After primary tumor and TDLN resection, inflamed distant LNs (metastases-free) were detected in head and neck cancer patients treated by neoadjuvant ICB (figure 5). Strikingly, compared to systemic administration, delivery of ICB to distant LNs achieves better response, after TDLN dissection (figure 6).
Conclusions Fluid exploits alternative interstitial transport pathways to adjacent basins, which can lead to immune responses occurring distally with the disruption of local fluid drainage. Thus, ICB efficacy is not reliant solely on the presence of the original TDLNs, and ICB can be effective against locoregional recurrence even after TDLN dissection.
Acknowledgements This work was financially supported by grants from NIH (K00CA234940 to H.Z.; F32CA275298 to M.J.O.; R21AI097745, R01CA214913, R01HL128168, R01CA284372, and R01CA284603 to T.P.P.), the Rullo Family MGH Research Scholar Award (T.P.P.), Walter Benjamin Programme, Deutsche Forschunsgemeinschaft Nr.: ME5486/1–2 (L.M.).
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