Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Immune-oncology, BioXcel Therapeutics Inc, New Haven, Connecticut, USA.
J Immunother Cancer. 2021 Nov;9(11). doi: 10.1136/jitc-2021-002837.
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC's extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, 'cold') tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.
We examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.
In both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.
These findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in 'cold' tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.
预计到 2030 年，胰腺癌（PDAC）将成为美国第二大癌症死亡原因。由于 PDAC 广泛的免疫抑制微环境和免疫浸润不良，免疫检查点抑制剂无法控制大多数 PDAC 肿瘤，这种表型也见于其他非炎症（即“冷”）肿瘤。寻找增强 PDAC 免疫疗法疗效的新方法至关重要。二肽基肽酶（DPP）抑制可以增强其他癌症类型的免疫疗法疗效；然而，DPP 抑制对 PDAC 肿瘤的影响仍未得到探索。
我们使用 C57BL/6 小鼠中的 mT3-2D 和 Pan02 皮下同源小鼠模型，研究了口服小分子 DPP 抑制剂（BXCL701）对 PDAC 肿瘤生长的影响。我们使用 RNAseq、免疫组织化学、细胞因子评估和流式细胞术研究了 DPP 抑制对肿瘤免疫景观的影响。然后，我们测试了 BXCL701 是否增强了抗程序性细胞死亡蛋白 1（抗 PD-1）的疗效，并进行了免疫细胞耗竭和重新挑战研究，以探讨细胞毒性免疫细胞与联合治疗疗效的相关性。
在两种 PDAC 小鼠模型中，DPP 抑制均增强了 NK 和 T 细胞的免疫浸润并降低了肿瘤生长。DPP 抑制还增强了抗 PD-1 的疗效。双重抗 PD-1 和 BXCL701 治疗的疗效依赖于 CD8+T 细胞和 NK 细胞。接受这种联合治疗的小鼠产生了抗肿瘤免疫记忆，在重新暴露后清除了一些肿瘤。最后，我们使用癌症基因组图谱（TCGA）证明，人类 PDAC 肿瘤中 NK 细胞含量的增加，而不是 T 细胞含量的增加，与更长的总生存期相关。我们提出，广泛的 DPP 抑制通过两种机制增强抗肿瘤免疫反应：（1）DPP4 抑制增加了肿瘤中 CXCL9/10 的含量，从而招募了 CXCR3+NK 和 T 细胞，（2）DPP8/9 抑制激活了炎症小体，导致促炎细胞因子释放和 Th1 反应，进一步增强了 CXCL9/10-CXCR3 轴。
这些发现表明，使用 BXCL701 进行 DPP 抑制代表了一种增强肿瘤微环境免疫细胞含量以提高 PDAC 中抗 PD-1 疗效的药物策略，表明 BXCL701 可以增强“冷”肿瘤类型的免疫疗法疗效。这些发现还强调了 NK 细胞与 T 细胞一起在调节 PDAC 肿瘤生长中的潜在重要性。
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