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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MSK Authors
  1. Ross Levine
    668 Levine
  2. Xiaoping Chen
    7 Chen
  3. Sheng Feng Cai
    26 Cai
  4. Charles Rudin
    356 Rudin
  5. Nisargbhai Sanjaykumar Shah
    20 Shah
  6. Joseph Minhow Chan
    27 Chan
  7. Juan   Qiu
    12 Qiu
  8. Viola   Allaj
    23 Allaj
  9. Andrew Chow
    26 Chow
  10. Triparna Sen
    44 Sen
  11. Fathema Zannath Uddin
    17 Uddin
  12. Yingqian Zhan
    16 Zhan
  13. Parvathy Manoj
    13 Manoj
  14. Minh N Nguyen
    3 Nguyen
  15. Michael Liu
    1 Liu