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Mahadevan NR , Knelson EH , Wolff JO , Vajdi A , Saigi M , Campisi M , Hong D , Thai TC , Piel B , Han S , Reinhold BB , Duke-Cohan JS , Poitras MJ , Taus LJ , Lizotte PH , Portell A , Quadros V , Santucci AD , Murayama T , Canadas I , Kitajima S , Akitsu A , Fridrikh M , Watanabe H , Reardon B , Gokhale PC , Paweletz CP , Awad MM , Van Allen EM , Lako A , Wang XT , Chen B , Hong F , Sholl LM , Tolstorukov MY , Pfaff K , Janne PA , Gjini E , Edwards R , Rodig S , Reinherz EL , Oser MG , Barbie DA
Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity
Cancer Discov. 2021 Mar 11
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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.
Notes
2159-8290 Mahadevan, Navin R Knelson, Erik H Orcid: 0000-0003-4087-2017 Wolff, Jacquelyn O Vajdi, Amir Orcid: 0000-0001-8271-8566 Saigi, Maria Orcid: 0000-0001-5815-5388 Campisi, Marco Orcid: 0000-0002-9288-5285 Hong, Deli Thai, Tran C Piel, Brandon Han, Saemi Reinhold, Bruce B Duke-Cohan, Jonathan S Orcid: 0000-0002-9478-9609 Poitras, Michael J Taus, Luke J Orcid: 0000-0003-0512-2536 Lizotte, Patrick H Orcid: 0000-0001-9510-0036 Portell, Andrew Orcid: 0000-0002-0757-909x Quadros, Victor Orcid: 0000-0003-4054-8591 Santucci, Alison D Murayama, Takahiko Orcid: 0000-0003-0764-8646 Canadas, Israel Orcid: 0000-0001-6474-711x Kitajima, Shunsuke Akitsu, Aoi Fridrikh, Maya Watanabe, Hideo Orcid: 0000-0002-6017-6361 Reardon, Brendan Gokhale, Prafulla C Paweletz, Cloud P Awad, Mark M Van Allen, Eliezer M Lako, Ana Wang, Xi-Tao Chen, Benjamin Hong, Fangxin Sholl, Lynette M Orcid: 0000-0002-9532-9735 Tolstorukov, Michael Y Pfaff, Kathleen Janne, Pasi A Gjini, Evisa Orcid: 0000-0002-6951-9279 Edwards, Robin Rodig, Scott Reinherz, Ellis L Orcid: 0000-0003-1048-5526 Oser, Matthew G Barbie, David A Journal Article United States Cancer Discov. 2021 Mar 11:candisc.0913.2020. doi: 10.1158/2159-8290.CD-20-0913.