酪氨酸蛋白激酶ABL2调控肿瘤微环境中TGFβ表达介导非小细胞肺癌免疫逃逸的分子机制研究

The efficacy of PD-(L)1 inhibitor can be ameliorated by reverting the immunosuppressive state of tumor microenvironment (TME). In this grant, we intend to explore the underlying mechanism which regulate TME and search for interventional targets in NSCLC patients with primary drug resistance to PD-(L)1 inhibitor. We found that: 1) tyrosine kinase ABL2 was upregulated in NSCLC patients with primary drug resistance to PD-(L)1 inhibitor. 2) ABL2 increased the expression of TGFβ, which is an important regulatory factor in TME. 3) JunB, the potential substrate of ABL2, is a potential transcription factor of TGFβ. Therefore, we proposed that ABL2 may increase the expression and secretion of TGFβ in TME by activating JunB, then promote the conversion of Treg cells and MDSCs, thereby mediating the immune escape of NSCLC. In this grant, we intend to utilize in vivo and in vitro study to clarify the effect of ABL2 on TME. Further, we will also explore the mechanism by which ABL2 regulates the expression and secretion of TGFβ and the role of TGFβ in promoting the immune escape of NSCLC. Finally, we will elucidate the potential therapeutic effect in suppressing immune escape of NSCLC through combining ABL2 inhibitor and PD-1 inhibitor. By doing so, we hope to provide theoretical and experimental evidence for combinatorial immunotherapy strategies.

改善肿瘤微环境(TME)的免疫抑制状态可提高PD-(L)1抑制剂的疗效。本项目从PD-(L)1抑制剂原发耐药的NSCLC患者入手，在探索调控TME的机制、并寻找可干预的靶点的过程中，发现：1）酪氨酸激酶ABL2在PD-(L)1抑制剂原发耐药的NSCLC患者中高表达；2）ABL2促进TGFβ的表达，而TGFβ是TME中的重要调控因子；3）ABL2的潜在底物JunB是TGFβ潜在的转录因子。据此，我们提出：ABL2可能通过激活JunB，促进TGFβ表达并分泌至TME中，活化Treg细胞和MDSCs介导NSCLC的免疫逃逸。本项目拟进一步联合体内外实验，明确ABL2对TME的影响；探索ABL2调控TGFβ表达与分泌的机制，并获得TGFβ促进NSCLC免疫逃逸的关键证据；阐明联合ABL2抑制剂及PD-1抑制剂协同遏制免疫逃逸在NSCLC的潜在治疗作用，为制定新的免疫联合治疗策略提供理论与实验依据。

肺癌是世界范围内发病率和死亡率最高的恶性肿瘤，其中80%-85%的肺癌属于非小细胞肺癌（NSCLC）。超过一半的NSCLC患者初诊时已为晚期，内科治疗是主要的治疗手段。近年来，针对免疫检查点，尤其是PD-1/PD-L1的免疫治疗在NSCLC中取得了里程碑意义的进展。然而抗PD-(L)1单抗在NSCLC治疗的有效率仍较低，本项目拟探索新的免疫逃逸调控靶点，为克服抗PD-(L)1单抗耐药提供新思路。本研究中，我们从临床指标、临床研究出发，挖掘临床预测肿瘤微环境及免疫治疗疗效指标，明确肿瘤微环境在介导PD-(L)1抑制剂原发耐药中起重要作用，它可通过非依赖于PD-1/PD-L1通路的机制来促进肿瘤细胞的免疫逃逸。接着，我们从PD-(L)1抑制剂耐药的患者组织标本中入手，开展一系列的实验及分析，发现酪氨酸激酶ABL2在对抗PD-(L)1单抗原发耐药的NSCLC中高表达，与肿瘤的恶性度及NSCLC患者的不良预后密切相关，且可促进肿瘤生长与侵袭。进一步研究发现，ABL2可通过上调其转录因子JunB的活性，促进多功能生物学活性细胞因子TGFβ的表达及分泌进而影响肿瘤免疫微环境。本研究顺利开展实施预期研究内容，以临床病例、细胞模型及动物模型为研究对象，通过一系列体内外实验解密非小细胞肺癌细胞抗PD-(L)1免疫治疗原发耐药的发生机制，揭示ABL2-JunB-TGFβ信号轴在介导非小细胞肺癌免疫逃逸中的作用，为建立逆转抗PD-(L)1免疫治疗原发耐药的有效策略提供理论与实验依据。