Cancer immunotherapy responses persist after lymph node resection

Abstract

Due to the critical role of lymph nodes (LNs) in the initiation and maintenance of adaptive immune responses, it is unclear whether surgical removal or ablative radiation therapy of LNs should be performed in patients with metastatic LNs that will receive immunotherapy. Surgical removal of LNs to prevent metastatic recurrence, including sentinel lymph node biopsy (SLNB) and completion lymph node dissection (CLND), are performed in routine practice. However, removing LNs eliminates opportunities for generating anti-cancer immune responses that are enhanced with immune checkpoint blockade (ICB). Balancing the potential risks and benefits of LN surgery is necessary to maximize outcomes for patients. In contrast to mouse studies using ectopic tumor implantation, the phase III clinical trialNCT00636168found patients with completely resected stage III melanoma (primary tumor, sentinel LNs and disease-related LNs all removed) still benefited from anti-CTLA4 inhibition. Our retrospective analysis demonstrated that stage III melanoma patients with SLNB or CLND have similar response to anti-PD1 inhibition. Using orthotopic murine mammary carcinoma and melanoma that have spontaneous LN metastases, we show that responses to ICB persist in mice after resection of TDLNs. Mechanistically, after disruption of normal lymphatic drainage, antigen can access adjacent lymphatic basins (lymphosomes) and be transported to distant LNs, which extends the responsiveness to ICB. By evaluating head and neck cancer patients treated by neoadjuvant durvalumab and irradiation, we show that distant LNs remain reactive in the absence of metastatic disease in ICB responder patients after tumor and disease related-LN resection, indicating anti-cancer immune reactions occur in distant LNs after TDLN removal in patients. Additionally, after TDLN dissection in mouse models, ICB delivered to distant LNs generated greater survival benefit, compared to systemic administration. In complete responders, anti-tumor immune memory induced by ICB was systemic rather than confined within lymphoid organs. Based on these findings, we constructed a computational model to predict free antigen trafficking in patients that will undergo LN dissection. Collectively, we propose that ICB efficacy persists in tumors of the trunk and extremities after removing original TDLNs because antigen can be transported through interstitial tissues to adjacent lymphosomes to gain access to alternative LNs, where anti-cancer immune responses can be generated and maintained.