Ratnam Nivedita M, Sonnemann Heather M, Frederico Stephen C, Chen Huanwen, Hutchinson Marsha-Kay N D, Dowdy Tyrone, Reid Caitlin M, Jung Jinkyu, Zhang Wei, Song Hua, Zhang Meili, Davis Dionne, Larion Mioara, Giles Amber J, Gilbert Mark R
Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, United States.
Front Oncol. 2021 Jul 15;11:719091. doi: 10.3389/fonc.2021.719091. eCollection 2021.
Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3 T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.
胶质母细胞瘤（GBM）是一种侵袭性脑恶性肿瘤，预后很差。随着越来越多的证据反驳脑免疫豁免，人们对研究免疫治疗策略来治疗中枢神经系统（CNS）癌症产生了浓厚兴趣。不幸的是，研究免疫治疗方案的临床研究取得的成功有限，引发了关于免疫治疗对这些癌症适用性的质疑。肿瘤浸润淋巴细胞（TILs）的固有数量不足以及全身循环T细胞向CNS的有限迁移可能导致对免疫治疗的反应不佳。TILs的这种缺乏与促进免疫细胞向肿瘤移动（趋化作用）的基因发生表观遗传沉默的发现一致。在本研究中，我们评估了GSK126（一种可透过血脑屏障（BBB）的EZH2小分子抑制剂）通过对T细胞趋化作用的表观遗传抑制来逆转GBM免疫逃逸的能力。我们还评估了该药物与抗PD-1治疗联合使用对同基因小鼠模型中肿瘤生长、生存和T细胞浸润的疗效。GSK126逆转了小鼠和人类GBM细胞系中的H3K27me。当与抗PD-1治疗联合使用时，观察到肿瘤中活化T细胞浸润显著增加。这导致免疫健全的同基因GBM小鼠模型的皮下和颅内肿瘤的肿瘤生长减少且生存期延长。此外，在引流淋巴结中也观察到CXCR3 T细胞显著增加，表明它们准备迁移到肿瘤。对GSK126作用机制的进一步研究揭示了其促进肿瘤细胞表达IFN-γ驱动的趋化因子CXCL9和CXCL10的能力，这些趋化因子可引导T细胞迁移，而不直接影响T细胞成熟和/或增殖。在免疫缺陷的SCID小鼠中，单药或联合用药均未获得生存益处，这表明GSK126在GBM中的治疗效果主要由淋巴细胞驱动。综上所述，我们的数据表明，在胶质母细胞瘤中，使用GSK126进行表观遗传调控可通过逆转使免疫细胞逃逸的表观遗传变化来改善当前的免疫治疗策略，从而增强免疫细胞向肿瘤的迁移。
