Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have transformed the treatment paradigm for head and neck squamous cell carcinoma (HNSCC). Although ICIs generate durable antitumor responses, the mechanisms that reinforce long-term immune memory and prevent recurrence remain incompletely understood. This understanding is increasingly critical as neoadjuvant immunotherapy gains traction in clinical practice.
This study aims to elucidate the mechanisms of durable antitumor immune memory in a preclinical HNSCC model and in clinical biospecimens from HNSCC patients undergoing neoadjuvant ICI to draw translational insights into how ICI shapes the immune macroenvironment to foster sustained antitumor immunity.
Using a tobacco-associated HNSCC model (4MOSC1) that closely mirrors human head and neck cancer biology, we established protocols to achieve durable immunity following ICI treatment, paralleling the efficacy seen in classical vaccination models. To enable precise spatiotemporal labeling of immune effector cells and investigate mechanisms of durable anticancer responses, we utilized a tamoxifen-inducible reporter model. Clinical biospecimens from patients receiving neoadjuvant ICI, including matched tumor, sentinel lymph node, ipsilateral non-sentinel lymph node, and contralateral non-sentinel lymph node, were analyzed. To assess the role of tumor-draining lymphatics, we performed selective ablation of regional lymphatics in advance of tumor rechallenge. To evaluate the utility of adjuvant ICI after complete response to upfront ICI, we conducted carcinogen challenges at the primary tumor site after complete response.
In clinical biospecimen, clonotypes identified in primary tumors after neoadjuvant ICI were represented not only in the sentinel lymph node but also throughout all regional lymphatics, mirroring our preclinical findings and underscoring the systemic impact of ICI therapy on T cell distribution. In the preclinical model, CD8 T cells with a progenitor exhausted (Tpex) phenotype circulated systemically following complete response, mobilized rapidly to the site of tumor rechallenge, and were retained there to mediate a robust antitumor response. Notably, these Tpex cells demonstrated effective tumor rejection, with their activity unaided by subsequent adjuvant ICI.
We present a clinically relevant model of complete pathologic response to neoadjuvant ICI, offering an opportunity to investigate the mechanisms underlying durable immune memory after neoadjuvant treatment. As in clinical biospecimens, neoadjuvant ICI leads to a rapid accumulation of antitumor-specific T cells with a Tpex phenotype that are long-lived and capable of mediating tumor rejection and whose activity is unaided by adjuvant ICI. Overall, this work raises the possibility that adjuvant ICI may be unnecessary in complete responders and that future work should focus on the activity of long-lived CD8 Tpex memory cells.