Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used

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.

Sentinel Lymph Node in Non-Small Cell Lung Cancer: Assessment of Feasibility and Safety by Near-Infrared Fluorescence Imaging and Clinical Consequences

“…Several animal studies have shown that the primary site of tumor-specific T-cell generation is the lymph node draining the tumor [ 41 , 42 , 43 ]. A study carried out on murine models with resectable but micrometastatic NSCLC aimed to determine the impact of the resection of lymph nodes draining the tumor (spotted by infrared fluorescence) on the development of pulmonary metastases [ 44 ]. It has been shown that the median survival after surgery was statistically better in the group without lymph node resection than in the group with resection of lymph nodes draining the tumor.…”

What is the appropriate “first lymph node” in the era of segmentectomy for non-small cell lung cancer?

“…These results could change the practice of segmentectomy in the future with systematic intraoperative confirmation by frozen section, guided by a successful identification of the sentinel lymph node. Finally, in the era of immunotherapy, the performance of a systematic lymph node dissection in patients whose sentinel lymph node is not invaded (confirmed with frozen analysis) must be put into perspective in view of the possibility of peri-operative effective immunotherapy treatment ( 10 ).…”

Lymph node dissection in lung cancer surgery

“…This data highlights the TDLN as a key site of immune regulation and control over the tumor microenvironment; thus, expanded dissection of the said nodes may lead to immune impairment due to less antigen exposure and immune priming. Further murine data were generated ( 31 ) from a metastatic lung cancer model where the primary subcutaneous tumors were resected with associated draining lymph nodes (dLN) remaining intact, completely resected, or partially resected. The median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days) compared to when lymph nodes remained intact (>88 days; p < 0.05).…”