Senent Yaiza, Fresquet Vicente, Jiménez Victoria, Valencia Karmele, Exposito Francisco, Martín-Úriz Patxi San, Camps Gracián, Fernández-Pierola Eva, de Córdoba Borja Ruiz-Fernández, González-Huarriz Marisol, Tamayo Ibon, Remírez Ana, Moreno Haritz, Serrano Diego, Ajona Daniel, Alonso Marta M, Lecanda Fernando, Pineda-Lucena Antonio, Prósper Felipe, Sanmamed Miguel F, Calvo Alfonso, Martinez-Climent Jose A, Pio Ruben
Program in Solid Tumors, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), CIMA Building, Pio XII 55, 31008, Pamplona, Spain.
Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
Mol Cancer. 2025 May 30;24(1):154. doi: 10.1186/s12943-025-02352-4.
Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models. Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses both in human and mouse solid tumor cell lines. This unique BCL-XL dependency was in clear contrast to hematological malignancies, which are largely dependent on BCL2 or MCL1 inhibition under epigenetic drug treatment. Mechanistically, co-targeting of epigenetic regulators and BCL-XL induced expression of endogenous retroelements that led to immunogenic cell death. We thus hypothesized that this response may sensitize tumor cells to immune checkpoint blockade (ICB). Accordingly, treatment with a triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody in vivo reduced tumor growth and prolonged overall survival in a panel of murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, as well as in an immunocompetent human colon cancer model. Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors.
表观遗传调节剂与促凋亡药物联合使用已成为血液系统恶性肿瘤的标准治疗方法。相反，这些联合用药在实体瘤中未能显示出临床疗效。为了解决这一差异，我们对表观遗传抑制剂与BH3模拟物联合使用的抗肿瘤活性进行了全面分析，BH3模拟物可阻断来自患者和小鼠模型的大量实体瘤细胞系中的抗凋亡蛋白BCL-XL、BCL2或MCL1。用靶向DNA甲基转移酶、组蛋白甲基转移酶和组蛋白脱乙酰酶的表观遗传药物与BCL-XL抑制剂联合治疗，在人和小鼠实体瘤细胞系中均产生了显著的体外协同反应。这种独特的对BCL-XL的依赖性与血液系统恶性肿瘤形成鲜明对比，血液系统恶性肿瘤在表观遗传药物治疗下主要依赖于BCL2或MCL1的抑制。从机制上讲，表观遗传调节因子和BCL-XL的共同靶向诱导了内源性逆转录元件的表达，从而导致免疫原性细胞死亡。因此，我们推测这种反应可能使肿瘤细胞对免疫检查点阻断（ICB）敏感。相应地，在体内用表观遗传和BCL-XL抑制剂与抗PD-1单克隆抗体的三联组合治疗，在一组小鼠同基因和原位肺癌、结直肠癌、乳腺癌、黑色素瘤和胶质母细胞瘤模型以及免疫健全的人类结肠癌模型中，可减少肿瘤生长并延长总生存期。通过对肿瘤微环境进行流式细胞术和单细胞RNA测序，我们发现三联疗法的广泛活性依赖于具有细胞毒性潜力的T细胞和NK细胞的扩增、M1/M2巨噬细胞比例的增加以及免疫抑制性调节性T细胞、树突状细胞和B淋巴细胞的减少。总之，我们报告了一种将表观遗传和BCL-XL抑制剂与ICB联合使用的新方案，该方案在多种实体瘤临床前模型中产生了强大的抗肿瘤反应。
