Spatiotemporal molecular elucidation of radiation-induced tumor microenvironment remodeling to en-hance immunotherapy in head and neck cancer

Recently we showed in HNSCC models that effective checkpoint blockade is dependent upon intact lymphatic drainage for dendritic cell trafficking and that elective nodal radiation abrogated the effectiveness of immunotherapy, possibly explaining the lack of efficacy seen in prior studies. Neoadjuvant immunotherapy preserves draining lymphatics, however, emerging trials testing PD-1i prior to surgery have documented major pathological response rates of only 5%. To enhance the effectiveness of single agent PD-1i, improve clinical outcomes and explore the immunomodulatory capacity of hypofractionated radiation, we recently completed a first in human phase I trial testing neoadjvuant immunoradiotherapy (NIRT) in locally advanced HPV+ and HPV- HNSCC patients. Patients received nivolumab x 3 doses in combination with stereotactic body radiation therapy (SBRT) to gross tumor volume of 8Gy x5 or 8Gy x3, followed by definitive surgical resection. Astonishingly, the pathologic complete response rate in HPV+ patients was 90% and no patient required adjuvant radiation or chemoradiation. A cohort of 5 patients with stage III-IVA HPV-negative HNSCC treated with 8GyX3 plus nivolumab demonstrated a 60% major pathologic (>25%) response and clinical to pathologic downstaging of 100%. Transcriptional signatures from these surgical specimens compared to baseline are characterized by increased phagocytic and macrophage activation pathways, Th1 and Th2 cell differentiation, antigen presentation and peptide loading onto MHC class I, as well as a loss of cell proliferation pathways that are distinctly different from those treated with radiation alone, strongly suggesting a synergistic effect. Given our previous work showing that prognosis of patients with HPV- HNSCC is significantly affected by spatial interactions between the immune effector and suppressor cells in the tumor microenvironment (TME), particularly tumor-reactive, antigen-specific CD8 T-cells, we hypothesize that preservation of immunologic function in regional draining lymph nodes during NIRT will improve pathologic response by enhancing anti-tumor immune cell priming, and thereby immune-mediated killing of tumor cells. To test this hypothesis, we recently launched a phase 2 neoadjuvant clinical trial of SBRT 8Gy x3 + pembrolizumab - in stage III-IVA HPV- HNSCC patients that uniquely includes preoperative sentinel lymph node biopsy at the time of definitive surgery. The aims of these proposed studies are to 1) Determine whether pathologic response to NIRT is associated with immune cell activation and priming of the anti-tumor response in the sentinel lymph nodes; and 2) use recently developed next-generation multi-omic spatiotemporal models to test the hypothesis that NIRT induces TME remodeling and enhances T-cell infiltration in primary HNSCC. Successful completion of these aims will elucidate the mechanisms responsible for tumor control in responders and non-responders, potentially leading to the development of a predictive biomarker and novel targets for immune modulation. Project Number: 1R01CA301042-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Richard Bell (+3 co-PIs) | Institution: PROVIDENCE HEALTH & SERVICES - OREGON, RENTON, WA | Award Amount: $715,710 | Activity Code: R01 | Study Section: Translational Immuno-oncology Study Section[TIO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298415