Pharmacological inhibition of CDK4/6 augments long-term anti-tumor immunity through the induction of T cell memory [9_RNAseq_in_vitro_human_LeY_CAR]

Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity. RNA sequencing of human Lewis Y CAR T cells CD3-activated in vitro for 8 days and treated for 7 days with DMSO/palbociclib in duplicate

细胞周期蛋白依赖性激酶4/6（cyclin dependent kinases 4 and 6，CDK4/6）小分子抑制剂是获批用于激素受体阳性乳腺癌的治疗药物，目前正针对多种其他癌症类型开展数百项临床试验评估。此类抑制剂的临床成功主要归因于已明确的肿瘤内在细胞静止机制，但其作为免疫调节因子的新兴作用尚未得到充分阐释。本研究通过整合表观基因组学、转录组学与蛋白质组学分析，揭示了CDK4/6抑制剂可促进免疫T细胞记忆表型与功能获得的全新作用机制。在小鼠模型中，短期CDK4/6抑制剂预处理可诱导长期内源性抗肿瘤T细胞免疫应答，增强嵌合抗原受体（chimeric antigen receptor，CAR）T细胞的存续能力与治疗功效，并诱导成视网膜细胞瘤蛋白（Retinoblastoma protein，RB）依赖型T细胞表型，该表型可助力黑色素瘤患者对免疫检查点阻断疗法产生良好应答。综上，上述机制层面的研究发现显著拓展了CDK4/6抑制剂作为增强抗肿瘤T细胞免疫的临床工具的潜在应用价值。本数据集针对体外经CD3激活8天、并用二甲基亚砜（dimethyl sulfoxide，DMSO）/帕博西尼（palbociclib）处理7天的人路易斯Y（Lewis Y）嵌合抗原受体T细胞进行了重复RNA测序实验（每组设置两份生物学重复样本）。