Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma
Abstract 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 necessecita...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01813-y |
| _version_ | 1797769622505652224 |
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| author | Shailendra K. Gautam Surinder K. Batra Maneesh Jain |
| author_facet | Shailendra K. Gautam Surinder K. Batra Maneesh Jain |
| author_sort | Shailendra K. Gautam |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T21:10:44Z |
| format | Article |
| id | doaj.art-277a78d2627e41a68e7c27e6ea3ff395 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-12T21:10:44Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-277a78d2627e41a68e7c27e6ea3ff3952023-07-30T11:09:23ZengBMCMolecular Cancer1476-45982023-07-0122113010.1186/s12943-023-01813-yMolecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinomaShailendra K. Gautam0Surinder K. Batra1Maneesh Jain2Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical CenterAbstract 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.https://doi.org/10.1186/s12943-023-01813-yImmunosuppressionPre-metastatic nicheExosomesNon-coding RNAMicrobiomeImmune and metabolic checkpoints |
| spellingShingle | Shailendra K. Gautam Surinder K. Batra Maneesh Jain Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma Molecular Cancer Immunosuppression Pre-metastatic niche Exosomes Non-coding RNA Microbiome Immune and metabolic checkpoints |
| title | Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| title_full | Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| title_fullStr | Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| title_short | Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| title_sort | molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma |
| topic | Immunosuppression Pre-metastatic niche Exosomes Non-coding RNA Microbiome Immune and metabolic checkpoints |
| url | https://doi.org/10.1186/s12943-023-01813-y |
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