Authors: Mahadevan, Navin R.; Knelson, Erik H.; Wolff, Jacquelyn O.; Vajdi, Amir; Saigi, Maria; Campisi, Marco; Hong, Deli; Thai, Tran C.; Piel, Brandon; Han, Saemi; Reinhold, Bruce B.; Duke-Cohan, Jonathan S.; Poitras, Michael J.; Taus, Luke J.; Lizotte, Patrick H.; Portell, Andrew; Quadros, Victor; Santucci, Alison D.; Murayama, Takahiko; Canadas, Israel; Kitajima, Shunsuke; Akitsu, Aoi; Fridrikh, Maya; Watanabe, Hideo; Reardon, Brendan; Gokhale, Prafulla C.; Paweletz, Cloud P.; Awad, Mark M.; Allen, Eliezer M. Van; Lako, Ana; Wang, Xi-Tao; Chen, Benjamin; Hong, Fangxin; Sholl, Lynette M.; Tolstorukov, Michael Y.; Pfaff, Kathleen; Janne, Pasi A.; Gjini, Evisa; Edwards, Robin; Rodig, Scott; Reinherz, Ellis L.; Oser, Matthew G.; Barbie, David A.
Online: https://cancerdiscovery.aacrjournals.org/content/early/2021/03/11/2159-8290.CD-20-0913
Issue: Cancer Discov. 2021 Mar 11;candisc.0913.2020.
Abstract
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with de-repression of STING. Transient EZH2 inhibition expands these non-neuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine non-neuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC’s intrinsic immunogenicity.
