Abstract IA25: Radiation as a way to flip the switch: Resistance to responder in HNSCC
Authors: Raben David 
Published: September 2020

Abstract
The de novo response to checkpoint inhibitors in advanced head and neck squamous cell cancer (HNSCC) remains at ~20%. Responders in this small cohort of patients also tend to eventually develop resistance. Efforts at simply combining more checkpoint inhibitors in the recurrent setting to overcome such resistance have also proven inadequate. Mounting evidence suggests that radiation may act as an in situ vaccine, boosting and stimulating antigen presentation, altering the tumor microenvironment (TME), enhancing interferon release, and upregulating PD-L1 expression that leads to enhanced response to checkpoint inhibitors. In patients where resistance has developed, radiation may hit the reset button and reconvert cancers to sensitivity again. The genomic landscape of HNSCC may play a role in looking to rationally combine novel agents already approved in breast and ovarian cancers with DNA damage repair defects, and the tumor mutational burden (TMB) may lend itself to predicting improved response to checkpoint inhibition. However, there is evidence that a high TMB might exist in HNSCC, similar to NSCLC, yet lack a proinflammatory TME that theoretically leads to reduced response to immune-modulating agents. In preclinical animal models of HNSCCs, radiation has been shown to enhance tumor responsiveness to checkpoint inhibitors by fueling the TME. Radiation initiates cell death and the production and release of cytokines and chemokines, such as CXCL9 and CXCL10, into the TME, which leads to infiltration of dendritic cells, macrophages, promotion of antigen-specific T-cell priming and cytotoxic T-cell infiltration and effector function. RT, however, can also modulate the infiltration of an immunosuppressive cell population in a dose-dependent manner. Critical to overcoming resistance or initiating a strong response to immune-enabling drugs may be how and when we deliver the radiation and the type of radiation utilized—hypofractionated or conventionally fractionated doses. High infiltration of Tregs and MDSCCs may contribute to radiation resistance along with resistance to immune-enabling drugs, so altering or depleting this population may lend itself to reversing or preventing resistance from developing. Preclinical evidence suggests that combining radiation with Treg depletion is far more effective than Treg depletion alone for improving response to anti-PD1 or PD-L1 therapy. This is just the beginning of our exploration of radiation’s ability to “flip the switch” and improve response to HNSCC that otherwise would be “cold” to checkpoint inhibition. Breaking down HNSCCs that utilize additional immunosuppressive options such as TGFb may also allow for combinatorial approaches to improve response. This lends itself to paradigm shifts in how we utilize radiation in locally advanced and the metastatic settings.
Citation Format: David Raben. Radiation as a way to flip the switch: Resistance to responder in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA25.