Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity

Navin R. Mahadevan, Erik H. Knelson, Jacquelyn O. Wolff, Amir Vajdi, Maria Saigí, Marco Campisi, Deli Hong, Tran C. Thai, Brandon Piel, Saemi Han, Bruce B. Reinhold, Jonathan S. Duke-Cohan, Michael J. Poitras, Luke J. Taus, Patrick H. Lizotte, Andrew Portell, Victor Quadros, Alison D. Santucci, Takahiko Murayama, Israel CañadasShunsuke Kitajima, Aoi Akitsu, Maya Fridrikh, Hideo Watanabe, Brendan Reardon, Prafulla C. Gokhale, Cloud P. Paweletz, Mark M. Awad, Eliezer M. Van Allen, Ana Lako, Xi Tao Wang, Benjamin Chen, Fangxin Hong, Lynette M. Sholl, Michael Y. Tolstorukov, Kathleen Pfaff, Pasi A. Jänne, Evisa Gjini, Robin Edwards, Scott Rodig, Ellis L. Reinherz, Matthew G. Oser, David A. Barbie

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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 derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine 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. Significance: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.

Original languageEnglish
Pages (from-to)1952-1969
Number of pages18
JournalCancer Discovery
Issue number8
StatePublished - Aug 2021


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