Targeting lysine-specific demethylase 1 rescues major histocompatibility complex class I antigen presentation and overcomes programmed death-ligand 1 blockade resistance in SCLC Journal Article
| Authors: | Nguyen, E. M.; Taniguchi, H.; Chan, J. M.; Zhan, Y. A.; Chen, X.; Qiu, J.; de Stanchina, E.; Allaj, V.; Shah, N. S.; Uddin, F.; Manoj, P.; Liu, M.; Cai, S. F.; Levine, R.; Quintanal-Villalonga, Á; Sen, T.; Chow, A.; Rudin, C. M. |
| Article Title: | Targeting lysine-specific demethylase 1 rescues major histocompatibility complex class I antigen presentation and overcomes programmed death-ligand 1 blockade resistance in SCLC |
| Abstract: | Introduction: SCLC is a highly aggressive neuroendocrine tumor that is characterized by early acquired therapeutic resistance and modest benefit from immune checkpoint blockade (ICB). Repression of the major histocompatibility complex class I (MHC-I) represents a key mechanism driving resistance to T cell-based immunotherapies. Methods: We evaluated the role of the lysine-specific demethylase 1 (LSD1) as a determinant of MHC-I expression, functional antigen presentation, and immune activation in SCLC in vitro and in vivo through evaluation of both human SCLC cell lines and immunocompetent mouse models. Results: We found that targeted inhibition of LSD1 in SCLC restores MHC-I cell surface expression and transcriptionally activates genes encoding the antigen presentation pathway. LSD1 inhibition further activates interferon signaling, induces tumor-intrinsic immunogenicity, and sensitizes SCLC cells to MHC-I–restricted T cell cytolysis. Combination of LSD1 inhibitor with ICB augments the antitumor immune response in refractory SCLC models. Together, these data define a role for LSD1 as a potent regulator of MHC-I antigen presentation and provide rationale for combinatory use of LSD1 inhibitors with ICB to improve therapeutic response in SCLC. Conclusions: Epigenetic silencing of MHC-I in SCLC contributes to its poor response to ICB. Our study identifies a previously uncharacterized role for LSD1 as a regulator of MHC-I antigen presentation in SCLC. LSD1 inhibition enables MHC-I–restricted T cell cytolysis, induces immune activation, and augments the antitumor immune response to ICB in SCLC. © 2022 International Association for the Study of Lung Cancer |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; genetics; interferon; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; protein targeting; lung neoplasms; cell protein; animal experiment; animal model; genetic transcription; in vivo study; in vitro study; pathology; tumor antigen; lung tumor; gene activation; antigen presentation; immune response; antigens, neoplasm; epigenetics; immunogenicity; hla antigen class 1; histocompatibility antigens class i; clinical evaluation; cytolysis; major histocompatibility complex; lysine; immunocompetence; small cell lung cancer; major histocompatibility antigen class 1; programmed death 1 ligand 1; histone demethylase; lysine specific demethylase 1; lsd1; histone demethylases; humans; human; female; article; lung cancer cell line; cd274 protein, human; b7-h1 antigen |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 17 |
| Issue: | 8 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2022-08-01 |
| Start Page: | 1014 |
| End Page: | 1031 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2022.05.014 |
| PUBMED: | 35691495 |
| PROVIDER: | scopus |
| PMCID: | PMC9357096 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 September 2022 -- Source: Scopus |
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