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Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma.
Gautam, Shailendra K; Batra, Surinder K; Jain, Maneesh.
Afiliação
  • Gautam SK; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA. shailendra.gautam@unmc.edu.
  • Batra SK; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • Jain M; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Cancer ; 22(1): 118, 2023 07 24.
Article em En | MEDLINE | ID: mdl-37488598
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Adenocarcinoma / Carcinoma Ductal Pancreático Tipo de estudo: Guideline / Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Adenocarcinoma / Carcinoma Ductal Pancreático Tipo de estudo: Guideline / Prognostic_studies Limite: Humans Idioma: En Revista: Mol Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos