Abstract A33: WEE1 inhibition induces antitumor immune responses in HPV16 E6/E7-driven head and neck cancer
Authors: Diab Ahmed , Kwak Jeff , Haussaini Yasser , Houghton McGarry , Clurman Bruce 
Published: December 2022

Abstract
Human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has already surpassed cervical cancer as a the most common HPV-related cancer in the United States. While HPV+ HNSCC patients have generally good survival, they suffer from life-long chemoradiotherapy-related morbidities. Current data is insufficient to inform de-intensification of standard chemoradiotherapy or the development of targeted therapies. FDA approval of immune checkpoint inhibitors (ICIs) as HNSCC treatment confirmed the power of harnessing the immune system for HNSCC therapy. However, response rates remain low and the favorable prognosis of HPV+ patients largely precludes them from receiving ICIs as part of standard care. Research aimed at elucidating the immune profile of HPV+ HNSCC is expected to help identify patients who would likely benefit from ICI therapy and to define new therapeutic targets in this patient population. Among novel therapeutic strategies, AZD1775 selectively inhibits the WEE1 cell cycle checkpoint kinase, causing premature mitosis and tumor cell death; this drug is being tested in clinical trials for patients with a variety of cancers including HNSCC. Our phase I clinical trial previously tested the safety and efficacy of WEE1i, given early as a neoadjuvant with standard chemotherapy. Two of the three extreme responders were HPV+ patients, suggesting a unique hypersensitivity of HPV+ HNSCC to WEE1i. In the preclinical setting, we recently showed that HPV16 E6/E7 oncoproteins sensitize HNSCC cells to WEE1i monotherapy through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. We also showed that elevated basal FOXM1 activity predisposes HPV+ HNSCC to AZD1775-induced toxicity. Of note, WEE1 inhibition was recently shown to augment the efficacy of ICIs and other immune-targeted therapies in several models of solid tumors. However, WEE1i is largely ineffective against HPV- syngeneic HNSCC models (carcinogen-induced, p53 deficient, Ras-mutated). To test if WEE1i monotherapy induces antitumor immunity in HPV+ HNSCC tumor models, we compared the response to AZD1775 in immunocompetent and immunodeficient mice bearing a transplantable murine HPV16E6, E7 and hRas (mEER)-driven tumors. AZD1775 monotherapy caused tumor regression and prolonged survival in the immunocompetent but not in the immunodeficient mice. To investigate whether AZD1775 alters the immune tumor microenvironment (TME), we performed flow cytometric immunophenotyping of mEER tumors following WEE1 inhibition. We observed a selective increase in the prevalence of CD8+ T cells in AZD1775-treated tumors, without a clear change in all other immune cell subsets examined, suggesting that WEE1 inhibition alters the composition of the TME of HPV+ HNSCC in favor of cytotoxic CD8+ T cells. These results may explain at least in-part the unique hypersensitivity of HPV+ HNSCC to AZD1775. Understanding how WEE1 inhibition modulates the TME may inform the development of HPV-specific combination therapies that include AZD1775 and immunotherapies.
Citation Format: Ahmed Diab, Jeff Kwak, Yasser Haussaini, McGarry Houghton, Bruce Clurman. WEE1 inhibition induces antitumor immune responses in HPV16 E6/E7-driven head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A33.