新型免疫负调控分子CD38介导PD-1/PD-L1免疫检查点阻断治疗耐受的机制研究

PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has ushered an unprecedented new era for cancer treatment in human history. PD-1/PD-L1 ICB therapy not only can lead to complete and durable treatment response in a sub fraction of cancer patients with relapsed and refractory diseases, but also will soon become widely accepted first line of treatment for highly prevalent major malignant diseases such as lung cancer. Nevertheless, due to high heterogeneity, plasticity and adaptation nature of cancers, cancer immunotherapy is also facing many challenges despite of major breakthroughs. There is an urgent need now to overcome and solve the problem of treatment resistance, especially therapy-induced treatment resistance, which requires more extensive research in both basic and clinical fronts. As a long-term systematic effort, our laboratory has developed a number of mouse models for human none small cell lung carcinomas (NSCLC) for both mechanistic and therapeutic investigations. Using these models, our recent work revealed that closely resembling the clinical observations, PD-L1 ICB therapy could effectively reverse T cell suppression in tumor microenvironment and lead to potent inhibition of tumor growth during the initial phase of treatment. However, a significant fraction of tumors developed resistance to anti-PD-L1 treatment and relapsed in the later stage. Transcriptional profiling by RNA deep sequencing and bioinformatics analysis showed that CD38 is one of the key genes whose expression was upregulated in those tumors developed treatment resistance. Further studies demonstrated that knocking down CD38 expression in the tumor cells or co-administering with anti-CD38 blocking antibodies could completely prevent resistance to anti-PD-L1 mono therapy, suggesting that CD38 could function as a previous unknown immune checkpoint molecule for negative regulation of anti-tumor T cell immune responses and mediate adaptive resistance to anti-PD-L1 therapy. Based on these important new findings, we propose to systematically investigate the role of CD38 in driving T cell suppression and exhaustion in tumor microenvironment through thorough molecular delineation of its biochemical activities and cellular functions. In conjunction, we will also investigate and determine the signaling pathways and mechanisms that are responsible for the upregulation of CD38 expression in tumor microenvironment induced by anti-PD-L1 therapy. The research we proposed here not only will provide deep mechanistic insights for better understanding the dynamic process of treatment resistance to immunotherapy, but also will help the new development of more effective combinatorial therapies targeting multiple immune checkpoint molecules.

PD-1/PD-L1免疫治疗已成功并广泛地应用于肺癌等恶性肿瘤临床治疗，然而肿瘤免疫治疗依旧面临挑战，获得性治疗耐受是当前亟需攻克的重大基础与临床难题。利用前期工作所建立的多种小鼠肺癌模型，我们发现与临床现象相同的PD-L1抗体可有效逆转肿瘤微环境中T细胞免疫抑制，对肺癌有出色的早期治疗效果，但后期多数肿瘤产生耐受。RNA深度测序等分析显示在治疗耐受肿瘤中CD38表达显著上调；进一步研究表明敲低CD38表达或联用CD38抗体可克服PD-L1治疗耐受，揭示CD38可作为免疫负调控分子介导获得性治疗耐受。本研究拟系统解析CD38抑制T细胞抗肿瘤免疫应答的细胞分子机制，阐明肿瘤微环境激活CD38上调表达的信号通路及其介导PD-L1治疗耐受的效应作用。本项目将促进对多重免疫检查点分子参与肿瘤免疫耐受动态过程及其机理的认识，为发展以免疫检查点阻断为核心的新型联合免疫治疗策略提供理论基础和新思路。

目前以PD-1/PD-L1抗体为核心的免疫检查点治疗通过重激活免疫细胞进而有效抑制肿瘤细胞，成为当今肿瘤治疗领域的重大突破。然而，免疫检查点治疗总体响应率较低且多数患者治疗一段时间后易出现获得性耐药，导致肿瘤复发甚至进展。因此，揭示并阐明免疫检查点治疗的耐药机制是临床亟待突破的关键性科学问题。申请人所在课题组长期致力于免疫检查点治疗耐药机制的探索及研究。在前期研究中，我们通过测序技术及生物信息学分析发现随着PD-L1抗体治疗出现耐药，肺癌细胞中CD38分子表达水平明显上调。CD38通过诱导免疫抑制性分子腺苷产生进而促进肿瘤免疫逃逸。进一步实验表明PD-L1抗体联合CD38抗体可有效延缓PD-L1抗体耐药。然而肿瘤细胞中CD38表达及其酶活性是否参与调控肿瘤细胞自身生存及肿瘤进展尚未有研究报道。本研究在前期研究基础上，进一步探索CD38调控肿瘤细胞自身生存的模式；确定CD38酶活性代谢产物或底物参与调节肿瘤细胞进展的分子机制和靶向CD38酶活性产物及底物存在的潜在治疗价值。通过本研究我们期望为CD38用于实体瘤治疗及联合免疫检查点治疗提供一定的理论与实验基础。