Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.
Contributed by Ute Burkhardt
ABSTRACT: Surgical removal of tumor-draining lymph nodes (tdLNs) is commonly performed in cancer patients. Here, we investigated whether immune checkpoint blockade (ICB) responses persist after resection of tdLNs, important sites for the initiation and maintenance of anti-cancer immunity. Melanoma patients remained responsive to programmed death 1 (PD-1) blockade after regional LN dissection. Similarly, ICB efficacy persisted after tdLN resection in orthotopic murine melanoma and mammary carcinoma models. Following tdLN removal, interstitial fluid containing soluble antigen was diverted through interstitial spaces across lymphosome boundaries to distant LNs, wherein cancer-derived antigen was acquired and presented to T cells by LN-resident type I conventional dendritic cells. These responses persisted after primary tumor resection and supported ICB-induced systemic immunity. Locoregional delivery of ICB to compensatory LNs enhanced anti-cancer responses after tdLN resection. Consistently, ICB responses in head and neck cancer patients were associated with reactive LNs at distant sites. Thus, antigen rerouting enables distant LNs to compensate for resected tdLNs and sustain anti-cancer immunity, including responses enhanced by immunotherapy.
