Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing
Journal Title
Clinical Cancer Research
Publication Type
epub ahead of print
Abstract
PURPOSE: The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically "cold" tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC. EXPERIMENTAL DESIGN: We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models. RESULTS: Bomedemstat potentiated responses to PD1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by interferon-ɣ and increased killing by tumor specific T cells in cell culture. CONCLUSIONS: LSD1 inhibition increased MHC-I expression and enhanced responses to PD1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard of care PD1 axis inhibition in SCLC.
Publisher
AACR
WEHI Research Division(s)
Cancer Biology And Stem Cells
PubMed ID
35920742
Terms of Use/Rights Notice
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Creation Date: 2022-08-08 09:15:50
Last Modified: 2022-08-08 09:43:47
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