Investigating the Role of B-cells in Durable Complete Responses to Immunotherapy in Head and Neck Cancer

While response rates to Checkpoint Blockade Immunotherapy (CBI) in Head and Neck Squamous Cell Carcinoma (HNSCC) are generally low, approximately 3-5% of patients show durable complete responses (dCR) and remain disease-free for at least two years following treatment. The mechanisms underlying these exceptional responses are unknown and may hold great promise for the development and refinement of immunotherapies. Remarkably, our recent work has determined that B-cell anti-tumor activity is associated with complete responses to CBI in HNSCC. However, the mechanisms underlying this increase in B-cell-mediated antibody activity, and the pathways by which B cells contribute to tumor control are understudied. The primary long-term goal of this project is to better understand the role of B cells in complete responses to CBI in HNSCC and thus improve immunotherapeutic approaches and increase complete response rates. The overall objectives of this application are to (i) test novel agents to harness and enhance B-cell mediated anti-tumor immunity, (ii) dissect the mechanism of action of B-cell mediated tumor control; and iii) define the specificity and identity of B-cell antibody profiles from patients with dCRs in HNSCC. The central hypothesis is that adaptive B cell activity is critically involved in complete responses to CBI in HNSCC and will be tested with three specific aims. Specific Aim 1 will determine the effects of CBI on B-cell activation and whether combinations of specific B-cell activators enhance anti-tumor immune responses and tumor control. Specific Aim 2 will identify B cell subtypes that mediate anti-tumor immunity, and dissect the mechanism of action of B- cells in orthotopic models of HNSCC. Specific Aim 3 will define the specificity and identify novel B-cell antibody repertoires that drive durable complete responses in HNSCC patients. The research proposed in this application is innovative due to the focus on durable and complete responses to cancer immunotherapy and the exploration of the mechanisms underlying these exceptional responses associated with the critical yet understudied role of B cells. The research is significant because it will identify specific B-cell agonists that can be used to enhance tumor control with CBI or XRT, elucidate the mechanism of action of B-cells and critical B-cell subtypes; and establish whether B-cell mediated antibody responses drive exceptional completed responses in HNSCC patients. Ultimately, these findings can be directly translated to improve outcomes for HNSCC patients. Project Number: 1R01CA292622-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Andrew Sharabi | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $650,597 | Activity Code: R01 | Study Section: Translational Immuno-oncology Study Section[TIO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297627