Immune-checkpoint (IC) modulators like the poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1) attenuate innate and adaptive immune responses and are potential therapeutic targets for diverse malignancies, including triple-negative breast cancer (TNBC). The retinoblastoma tumor suppressor, pRB, controls cell growth through E2F1-3 transcription factors, and its inactivation drives metastatic cancer, yet its effect on IC modulators is contentious. Here, we show that RB-loss and high E2F1/E2F2 signatures correlate with expression of PVR, CD274 (PD-L1 gene) and other IC modulators and that pRB represses whereas RB depletion and E2F1 induce PVR and CD274 in TNBC cells. Accordingly, the CDK4/6 inhibitor, palbociclib, suppresses both PVR and PD-L1 expression. Palbociclib also counteracts the effect of CDK4 on SPOP, leading to its depletion, but the overall effect of palbociclib is a net reduction in PD-L1 level. Hydrochloric acid, commonly used to solubilize palbociclib, counteracts its effect and induces PD-L1 expression. Remarkably, lactic acid, a by-product of glycolysis, also induces PD-L1 as well as PVR. Our results suggest a model in which CDK4/6 regulates PD-L1 turnover by promoting its transcription via pRB-E2F1 and degradation via SPOP and that the CDK4/6-pRB-E2F pathway couples cell proliferation with the induction of multiple innate and adaptive immunomodulators, with direct implications for cancer progression, anti-CDK4/6- and IC-therapies.

脊髓灰质炎病毒受体 (PVR) 和程序性死亡配体 1 (PD-L1) 等免疫检查点 (IC) 调节剂可减弱先天性和适应性免疫反应，是包括三阴性乳腺癌 (TNBC) 在内的多种恶性肿瘤的潜在治疗靶点。视网膜母细胞瘤肿瘤抑制因子 pRB 通过 E2F1-3 转录因子控制细胞生长，其失活会导致转移性癌症，但其对 IC 调节剂的影响存在争议。在这里，我们表明 RB 损失和高 E2F1/E2F2 特征与PVR、CD274 （PD-L1 基因）和其他 IC 调节剂的表达相关，并且 pRB 抑制而 RB 耗尽和 E2F1 诱导PVR和CD274在 TNBC 细胞中。因此，CDK4/6 抑制剂 palbociclib 抑制 PVR 和 PD-L1 的表达。Palbociclib 还抵消了 CDK4 对 SPOP 的影响，导致其耗尽，但 palbociclib 的总体效果是 PD-L1 水平的净降低。通常用于溶解 palbociclib 的盐酸会抵消其作用并诱导 PD-L1 表达。值得注意的是，乳酸是糖酵解的副产物，它也会诱导 PD-L1 和 PVR。我们的结果表明了一个模型，其中 CDK4/6 通过 pRB-E2F1 促进其转录和通过 SPOP 促进其降解来调节 PD-L1 转换，并且 CDK4/6-pRB-E2F 通路将细胞增殖与多种先天性和适应性免疫调节剂的诱导相结合，对癌症进展、抗 CDK4/6 和 IC 疗法有直接影响。