Neoadjuvant Immunoradiotherapy in a Tobacco-Signature Preclinical Oral Squamous Cell Carcinoma Model

Abstract

<h3>Purpose/Objective(s)</h3> PD-1 inhibition (PD1i) has demonstrated no benefit for locally advanced HNSCC, and emerging neoadjuvant PD1i window of opportunity yield promising but limited responses. Our preclinical work demonstrates that ablating tumor draining lymphatics compromises the response to immune-oncology (IO) therapy. In concert, a recently completed phase I trial investigating neoadjuvant immunoradiotherapy (NIRT) – 8Gy to gross tumor volume plus PD1i followed by surgery – for treatment-naïve HPV- HNSCC demonstrated a 60% major pathologic (>25%) response and clinical to pathologic downstaging of 100% (NCT03247712). Accordingly, we hypothesize that lymphatic-preserving immune oncology (IO) therapy can potentiate PD1i and promote antitumor immunity by enhancing immunosurveillance along the tumor-immune-lymphatic axis and reversing the suppressive tumor immune microenvironment (TIME). <h3>Materials/Methods</h3> To explore this, we employed our recently characterized tobacco-signature, orthotopic murine oral squamous cell carcinoma (OSCC) models, one of which matches the immune infiltrate and PD1i response of human OSCC and the other of which is immune-cold with no response to PD1i. Using these models, we delivered sequences of NIRT along with procedures to ablate tumor-draining lymph nodes (tdLNs) or lymphatic channels to characterize the immune mechanisms that optimize antitumor immunity and therapy response. <h3>Results</h3> We define a NIRT scheme that spares tumor lymphatics and leads to complete and durable immunity in our immune-responsive OSCC preclinical model. By ablating tumor-draining lymphatics, we find that tdLNs are critical for the NIRT response. Moreover, we interrupt draining lymphatics to the sentinel lymph node (SLN), mapped with an IRDye-tagged tilmanocept, to explore immunosurveillance across the tumor-immune-lymphatic axis. Lymphatic channel ablation blocks the tumor NIRT response and leads to a restriction of cytotoxic, tumor-antigen specific CD8 T cells from the TIME. Within tdLNs, we find that conventional type I dendritic cells are necessary for the NIRT response and enhanced following NIRT. Lastly, we find that NIRT reverses local immunosuppression by reducing myeloid derived suppressor cells within the TIME, potentiating PD1i and leading to complete response in our immune-cold model. <h3>Conclusion</h3> We demonstrate that targeting tumors with stereotactic radiation and PD1i while sparing draining lymphatics enhances anticancer immunity by promoting regional immunosurveillance and repolarizing local suppressive TIMEs, resulting in significantly improved responses. Overall, this work represents a paradigm-shift in the design of IO therapies, which can immediately inform the design of next-generation immune oncology trials for HNSCC.