Simultaneous inhibition of LSD1 and TGFβ enables eradication of poorly immunogenic tumors with Anti-PD-1 treatment

Journal article : Comment

Epigenetic regulators are a class of promising targets in combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGFβ expression, which exerts an inhibitory effect on T-cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation–induced T-cell infiltration. Importantly, concurrent depletion of LSD1 and TGFβ in combination with PD-1 blockade significantly increases both CD8+ T-cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor rechallenge. Thus, combining LSD1 inhibition with blockade of TGFβ and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors.

Authors: Sheng, W; Liu, Y; Chakraborty, D; Debo, B; Shi, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Cancer Discovery
• Volume: 11
• Issue: 8
• Pages: 1970-1981
• Publication date: 2021-03-09
• Acceptance date: 2021-03-04
• DOI: 10.1158/2159-8290.cd-20-0017
• EISSN: 2159-8290
• ISSN: 2159-8274
• Pmid: 33687985
• Language: English
• Keywords: FFR
• Subtype: Comment