Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Cancer. 2023 Jul 24;22(1):118. doi: 10.1186/s12943-023-01813-y.
Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.
免疫抑制是胰腺导管腺癌 (PDAC) 的标志，导致早期转移和患者生存不良。与局部肿瘤相比，目前的标准治疗方法未能改善转移性 PDAC 患者的生存，这需要探索新的治疗方法。虽然免疫疗法，如免疫检查点阻断 (ICB) 和治疗性疫苗，已成为某些癌症的有前途的治疗方式，但在 PDAC 中取得的反应有限。因此，必须探索调节免疫治疗反应不佳的特定机制。致癌突变、肿瘤分泌组、非编码 RNA 和肿瘤微生物组驱动的免疫抑制微环境在 PDAC 进展过程中持续存在，允许肿瘤细胞在局部生长和远处转移。逃避宿主免疫监视的转移性细胞在分子、免疫学和代谢特征上具有独特性。在趋化因子和外泌体的引导下，这些细胞转移到由局部常驻细胞、基质成纤维细胞和抑制性免疫细胞（如转移相关巨噬细胞、中性粒细胞和髓系来源的抑制细胞）组成的器官特异性前转移龛 (PMN)。转移性免疫微环境在基质和免疫细胞组成、功能和代谢方面与原发性肿瘤不同。迄今为止，已经确定了多个与原发性肿瘤不同的分子和代谢途径，这些途径削弱了免疫效应功能，使转移性 PDAC 的免疫治疗反应复杂化。本综述描述了促进 PDAC 转移进展和限制免疫治疗结果的主要免疫调节途径。总体而言，我们强调了归因于免疫抑制因素的治疗弱点，并讨论了靶向这些分子和免疫学“热点”是否可以改善 PDAC 免疫治疗的结果。
