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Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.


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 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.This article is highlighted in the In This Issue feature, p. 1861.

SUBMITTER: Mahadevan NR 

PROVIDER: S-EPMC8338750 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.

Mahadevan Navin R NR   Knelson Erik H EH   Wolff Jacquelyn O JO   Vajdi Amir A   Saigí Maria M   Campisi Marco M   Hong Deli D   Thai Tran C TC   Piel Brandon B   Han Saemi S   Reinhold Bruce B BB   Duke-Cohan Jonathan S JS   Poitras Michael J MJ   Taus Luke J LJ   Lizotte Patrick H PH   Portell Andrew A   Quadros Victor V   Santucci Alison D AD   Murayama Takahiko T   Cañadas Israel I   Kitajima Shunsuke S   Akitsu Aoi A   Fridrikh Maya M   Watanabe Hideo H   Reardon Brendan B   Gokhale Prafulla C PC   Paweletz Cloud P CP   Awad Mark M MM   Van Allen Eliezer M EM   Lako Ana A   Wang Xi-Tao XT   Chen Benjamin B   Hong Fangxin F   Sholl Lynette M LM   Tolstorukov Michael Y MY   Pfaff Kathleen K   Jänne Pasi A PA   Gjini Evisa E   Edwards Robin R   Rodig Scott S   Reinherz Ellis L EL   Oser Matthew G MG   Barbie David A DA  

Cancer discovery 20210311 8


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. <i>In vitro</i> modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition ex  ...[more]

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