Simultaneous Inhibition of LSD1 and TGFβ Enables Eradication of Poorly Immunogenic Tumors with Anti–PD-1 Treatment

Abstract

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. SignIficance: Cotargeting LSD1 and TGFβ cooperatively elevates intratumoral CD8+ T-cell infiltration and unleashes their cytotoxicity, leading to tumor eradication upon anti–PD-1 treatment. Our findings illustrate a duality of epigenetic perturbations in immunotherapy and implicate the combination of LSD1 inhibition with dual PD-1/TGFβ blockade in treating certain poorly immunogenic tumors. This article is highlighted in the In This Issue feature, p. 1861

Comprehensive Analysis Uncovers Prognostic and Immunogenic Characteristics of Cellular Senescence for Lung Adenocarcinoma

“…This result suggested that patients with higher SRS score might have an immunosuppressive tumor microenvironment, which prevented immune clearance of tumor cells. GSEA also showed that upregulation of the TGF-β-associated pathway, which has been widely reported as an important factor to restrain antitumor immunity (Mariathasan, et al, 2018;Sheng, et al, Cuollo, et al, 2020;Basisty, et al, 2020;Lau and David 2019). Third, as mentioned above, cellular senescence-related immune remodelling may explain the diminished efficacy of checkpoint blockade.…”

“…This result suggested that patients with higher SRS score might have an immunosuppressive tumor microenvironment, which prevented immune clearance of tumor cells. GSEA also showed that upregulation of the TGF-β-associated pathway, which has been widely reported as an important factor to restrain antitumor immunity ( Mariathasan, et al, 2018 ; Sheng, et al, 2021 ), was prominently enriched in the high-risk group. Second, to further explore the mechanisms of immune remodelling by the increasing burden of senescent cells in tumors, we uncovered that alterations of SASP could impact TIME establishment, which ultimately contributes to immune escape and provokes tumor development.…”

Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy

“…Next, the synergistic depletion of LSD1 and TGF-β in combination with immune checkpoint blockade ameliorates intratumoral CD8 T cell infiltration and effector functions, resulting in eradication of tumor and long-term protection from tumor re-challenge. 67 …”

Co-Expression of miR155 or LSD1 shRNA Increases the Anti-Tumor Functions of CD19 CAR-T Cells

“…LSD1 plays a critical role in the formation of transcriptional repressor complexes with histone deacetylase 1 and 2 and the RE1 silencing transcription factor co-repressor ( 42 ) and regulates gene activation and repression ( 43 ). Recent studies demonstrated that LSD1 inhibition is correlated with potent anti-tumor T cell immunity and enhanced T cell infiltration in the tumor microenvironment in mouse models ( 44 ). LSD1 plays an important role in the regulation of Th1 cell differentiation, and the inhibition of LSD1 in activated CD4+ T cells induced IFN-γ-producing Th1 cells ( 45 ), suggesting that LSD1 inhibition may be a potential strategy to improve Th1 cell differentiation and cytotoxic T cell immune function.…”