Targeting Lysine-Specific Demethylase 1 Rescues Major Histocompatibility Complex Class I Antigen Presentation and Overcomes Programmed Death-Ligand 1 Blockade Resistance in SCLC

J Thorac Oncol. 2022 Aug;17(8):1014-1031. doi: 10.1016/j.jtho.2022.05.014. Epub 2022 Jun 9.


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.

Keywords: Antigen presentation; Epigenetics; LSD1; Small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation*
  • Antigens, Neoplasm
  • B7-H1 Antigen
  • Genes, MHC Class I
  • Histocompatibility Antigens Class I* / genetics
  • Histone Demethylases* / genetics
  • Histone Demethylases* / metabolism
  • Humans
  • Lung Neoplasms* / pathology
  • Mice
  • Small Cell Lung Carcinoma* / pathology


  • Antigens, Neoplasm
  • B7-H1 Antigen
  • CD274 protein, human
  • Histocompatibility Antigens Class I
  • Histone Demethylases
  • KDM1A protein, human