Gamache Awndre, Conarroe Claire, Adair Sara, Bauer Todd, Padilla Frederic, Bullock Timothy N J
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, United States.
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States.
Front Cell Dev Biol. 2023 Apr 12;11:1173686. doi: 10.3389/fcell.2023.1173686. eCollection 2023.
Immune checkpoint blockade immunotherapy has radically changed patient outcomes in multiple cancer types. Pancreatic cancer is one of the notable exceptions, being protected from immunotherapy by a variety of mechanisms, including the presence of a dense stroma and immunosuppressive myeloid cells. Previous studies have demonstrated that CD40 stimulation can remodel the tumor microenvironment in a manner that promotes effector immune cell responses and can cooperate with immune checkpoint inhibition for durable tumor control mediated by T cells. Here we confirm the capability of this combination therapy to dramatically, and durably, control pancreatic cancer growth in an orthotopic model and that the immune memory to this cancer is primarily a function of CD4 T cells. We extend this understanding by demonstrating that recruitment of recently primed T cells from the draining lymph nodes is not necessary for the observed control, suggesting that the pre-existing intra-tumoral cells respond to the combination therapy. Further, we find that the efficacy of CD40 stimulation is not dependent upon CD70, which is commonly induced on dendritic cells in response to CD40 agonism. Finally, we find that directly targeting the receptor for CD70, CD27, in combination with the TLR3 agonist polyIC, provides some protection despite failing to increase the frequency of interferon gamma-secreting T cells.
免疫检查点阻断免疫疗法已从根本上改变了多种癌症类型患者的治疗结果。胰腺癌是一个显著的例外，它通过多种机制免受免疫疗法的影响，包括存在致密的基质和免疫抑制性髓样细胞。先前的研究表明，CD40刺激可以以促进效应免疫细胞反应的方式重塑肿瘤微环境，并且可以与免疫检查点抑制协同作用，以实现由T细胞介导的持久肿瘤控制。在此，我们证实了这种联合疗法在原位模型中显著且持久地控制胰腺癌生长的能力，并且对这种癌症的免疫记忆主要是CD4 T细胞的功能。我们通过证明从引流淋巴结募集最近激活的T细胞对于观察到的控制并非必要，扩展了这一认识，这表明肿瘤内预先存在的细胞对联合疗法有反应。此外，我们发现CD40刺激的疗效不依赖于CD70，CD70通常在树突状细胞上因CD40激动作用而被诱导。最后，我们发现直接靶向CD70的受体CD27，与TLR3激动剂聚肌胞苷酸联合使用，尽管未能增加分泌干扰素γ的T细胞频率，但仍提供了一定的保护作用。
