Election denial.

Top Line: Why head and neck squamous cell carcinoma (HNSCC) with all its hallmarks of immunogenicity has seen largely lackluster results with immune checkpoint inhibition remains an enigma.

The Study: Ready for a novel, thought-provoking hypothesis as to why? Standard elective nodal irradiation (ENI) may dampen the immune response in tumor-draining lymph nodes. In mouse models where all received immunotherapy but some received ablative radiation to gross tumor alone and others received standard conventionally-fractionated radiation to both the tumor and elective nodes, those receiving ENI demonstrated a much weaker systemic immune response based on detailed analyses of tumor, nodal, and serum immune markers. To confirm the importance of the draining lymph nodes, a similar reduction in immune response was observed when a lymph node dissection was performed in lieu of ENI. In contrast, tumor only radiation and immunotherapy resulted in excellent local and distant tumor control.  The problem was that this approach resulted in increased regional recurrence, which was the dominant pattern of failure. In other words, the reason elective nodal radiation has proved so effective for HNSCC is that it has a preponderance for failure in the draining lymph nodes. Interestingly, immunotherapy did not reduce nodal recurrence. Therefore, the negative immunogenic effects of nodal irradiation are outweighed by the reduction in regional recurrence. The study also suggested the sequencing of immunotherapy, ENI, and surgery may influence immunogenic response. Surgery after immunotherapy did not dampen systemic anti-tumor immunity. 

TBL: While elective nodal irradiation for HNSCC may actually dampen systemic immunity from immunotherapy, regional therapy remains essential in preventing regional recurrence. A better understanding of HNSCC immunity and the optimal sequencing of local, regional, and systemic therapy may improve treatment outcomes. | Darragh, Nat Commun 2022