Sulindac sensitizes colorectal cancer to anti-PD-L1 therapy

项目总结： 在过去的几十年里，结直肠癌(CRC)患者的总体生存率有了显著的提高， 但IV期结直肠癌患者的5年生存率仍低于14%。因此，当务之急是 需要开发更有效和更安全的治疗结直肠癌的方法。新型免疫检查点抑制物(ICI) 治疗方法开创了免疫治疗的新时代，并成为各种疾病的重要治疗选择。 实体瘤的症状。然而，ICIS仅对具有缺失错配修复(DMMR)的CRC患者有效，并且 微卫星高不稳定性(MSI-H)。对于大约85%携带熟练错配的结直肠癌患者 修复(PMMR)和微卫星稳定(MSS)或不稳定(MSI-L)癌，ICIS显示的临床益处不大。在……里面 在一项初步研究中，我们检测了小剂量舒林酸增强pMMR/MSS反应的有效性。 结直肠癌以抗PD-L1免疫治疗为主。利用同基因小鼠肿瘤模型和人源化患者来源 建立异种移植(PDX)小鼠模型，比较PD-L1抗体(Abs)、舒林酸在低剂量下的抑制作用 剂量，以及它们的组合对pMMR/MSS CRC的影响。我们的结果表明，用小鼠注射了 联合治疗显示肿瘤体积明显缩小，CD8+肿瘤细胞增加。 肿瘤组织中的浸润性淋巴细胞(TIL)。在研究其作用机制时，我们发现舒林酸 可以转录抑制PD-L1的表达，最终减少外体PD-L1释放到 发行量。由于胞外体PD-L1通常与循环中的PD-L1抗体结合并耗尽， 舒林酸和PD-L1抗体可以潜在地增强抗体募集。因此，我们假设低- 剂量舒林酸可使结直肠癌对抗PD-L1治疗增敏。在本申请中，我们提出了三个具体目标 系统、严谨地研究舒林酸的这一新活性。在目标1中，我们将通过以下方式研究这些机制 哪个舒林酸使CRC对抗PD-L1治疗敏感，特别是舒林酸如何调节PD-L1的表达； 目的2，我们将使用创新和强大的人源化PDX模型来研究小剂量舒林酸的体内疗效 在加强抗PD-L1治疗方面的作用。MSS和MSI CRC模型都将进行测试。在目标3中，我们将调查 舒林酸联合抗PD-L1治疗能否阻断结直肠癌的转移。自.以来 舒林酸和PD-L1抗体是FDA批准的药物，它们的安全性和毒性特征一直很好 我们希望我们的研究的成功将迅速促进第二阶段临床试验，以调查 舒林酸增强的抗PD-L1治疗在结直肠癌中的应用及解决穷人的重要临床挑战 大多数结直肠癌患者对ICI治疗的反应。

Project Summary: The overall survival of colorectal cancer (CRC) patients has improved significantly over the past few decades, but the 5-year survival rate for patients with stage IV CRC remains below 14%. Therefore, there is an urgent need to develop more effective and safer treatments against CRC. New immune checkpoint inhibitor (ICI) therapies have ushered in a new era of immunotherapy and emerged as important treatment options for a variety of solid tumors. However, ICIs are only effective in CRC patients with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H). For the approximately 85% of CRC patients who carry proficient mismatch repair (pMMR) and microsatellite stable (MSS) or instability-low (MSI-L) CRCs, ICIs show little clinical benefit. In a preliminary study, we examined the efficacy of low-dose sulindac in enhancing the response of pMMR/MSS CRC to anti-PD-L1 immunotherapy. Utilizing a syngeneic mouse tumor model and a humanized patient-derived xenograft (PDX) mouse model, we compared the inhibitory effects of PD-L1 antibodies (Abs), sulindac at low doses, and their combination on pMMR/MSS CRC. Our results demonstrated that the mice treated with the combination therapy showed a significant reduction in tumor volume, along with an increase of CD8+ tumor- infiltrating lymphocytes (TILs) in tumor tissues. While studying the mechanism of action, we found that sulindac could transcriptionally inhibit PD-L1 expression and ultimately reduce the release of exosomal PD-L1 into the circulation. As exosomal PD-L1 normally binds to and depletes circulating PD-L1 Abs, the combination of sulindac and the PD-L1 Ab can potentially enhance antibody recruitment. Therefore, we hypothesize that low- dose sulindac can sensitize CRC to anti-PD-L1 therapy. In this application, we propose three specific aims to systematically and rigorously investigate this new activity of sulindac. In Aim 1, we will study the mechanisms by which sulindac sensitizes CRC to anti-PD-L1 therapy, specifically how sulindac regulates PD-L1 expression; in Aim 2, we will use innovative and robust humanized PDX models to study the in vivo efficacy of low-dose sulindac in enhancing anti-PD-L1 therapy. Both MSS and MSI CRC models will be tested. In Aim 3, we will investigate whether the combination of sulindac and anti-PD-L1 therapy can block the metastatic progression of CRC. Since sulindac and PD-L1 antibodies are FDA-approved drugs and their safety and toxicity profiles have been well- documented, we hope that the success of our study will rapidly facilitate Phase II clinical trials to investigate the utility of sulindac-enhanced anti-PD-L1 therapy in CRC and address the important clinical challenge of poor response to ICI therapy in the majority of CRC patients.