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 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.

Prognostic value of the systemic immuno-inflammatory index in critically ill patients with vertebral fractures

“…[ 26 ] SII level reflects the inflammatory activation status and is a routinely used biomarker of systemic inflammatory activity. [ 27 , 28 ] Patients exhibiting elevated SII levels often develop neutrophilia, thrombocytosis, or lymphocytopenia. Increased secretion of pro-inflammatory cytokines, neutrophil aggregation, and impaired alveolar-capillary barriers may contribute to the pathogenesis of vertebral fractures.…”

Targeting neutrophils: Mechanism and advances in cancer therapy

“…The premetastatic niche plays a crucial role in facilitating the colonisation of cancer cells in distant organs, 39 and has also has attracted much attention in cancer‐targeting treatment. 40 , 41 Premetastatic niches, which are the foundation of tumour metastasis, are no longer considered to take place in one location. Circulating tumour cells are captured and vascular permeability is increased.…”

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…Immunosuppression is a hallmark of PDAC which contributes to early metastasis and poor patient survival. Substantial investigations have indicated that PDAC-secreted exosomes could induce the formation of PMNs in the liver, the most common site for PDAC metastasis, through molecular and metabolic regulation of immunosuppression [ 286 , 287 ].…”