Background Oncologically-sound standard of care therapy often indicates ablation of draining lymphatic basins to eradicate repositories of metastatic disease. However, emerging cancer immunotherapies often necessitate intact secondary lymphoid organs to achieve maximum effect. Therefore, multimodal immune-oncology (IO) therapeutic approaches introduce an inherent paradox into the clinical management of the cancer patient: how to reconcile the clinical benefit of lymphatic ablation with the destruction of an indispensable immune organ.

Methods Here, we leverage a novel preclinical model of tobacco-signature head and neck squamous cell carcinoma (HNSCC) to examine the impact of lymphatic ablation on the efficacy of immunotherapy and to identify sequences of therapy that maximize durable response without compromising oncologically-sound standard of care therapy.

Results We show that cervical lymphatic ablation in tumor bearing animals abolishes the response to CTLA- 4 blockade by eradicating lymph-node associated conventional dendritic cells and restricting CD8 T cell priming and subsequent tumor infiltration. By modelling recurrent HNSCC, we find that upfront, elective cervical lymphatic ablation eliminates the tumor response to adjuvant CTLA-4 blockade in contrast to a lymphatic-sparing approach, which preserves sensitivity to CTLA-4 blockade. In the neoadjuvant setting, we show that delayed, but not early, cervical lymphatic ablation leads to durable response after CTLA-4 blockade. Lastly, we demonstrate that a successful tumor response to CTLA-4 blockade begets long-lasting immunologic memory, resistant to delayed cervical lymphatic ablation.

Conclusions Collectively, this work addresses an inherent paradox in the delivery of combination IO therapy, informs optimal sequencing of multimodal therapy and affords a premise for the introduction of CTLA-4 blockade into the clinical management of HNSCC.