Fear et al. developed murine lung cancer models in which metastatic disease, seeded by tumor cells injected i.v. on the day of surgical removal of a primary s.c. tumor, arose early in the outermost layer of the lung, and later as tumor nodules in the lung. Host survival was improved if i.v. tumor cell injection was 7-14 days after s.c. tumor inoculation, and if dLNs were not completely resected at the time of surgery; host survival was inhibited by depletion of CD8+ T cells. Anti-CTLA-4 treatment controlled primary s.c. tumors, but not metastases. Anti-PD-1 + CD40 agonist treatment controlled primary tumors and metastatic disease, even in mice that had undergone dLN resection.
Contributed by Paula Hochman
ABSTRACT: Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (>_88 days; p_<_0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.