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.

Keywords: Exosomes; Immune and metabolic checkpoints; Immunosuppression; Microbiome; Non-coding RNA; Pre-metastatic niche.

Fig. 1

Metastatic cascade during PDAC progression. A Cells disseminating from primary tumors preferentially metastasize to different organs such as the liver (A) and lung (B). C Several TME factors such as hypoxia, autophagy, and suppressive cytokines and chemokines influence tumor cells to undergo EMT and gain immunosuppressive phenotype with reduced expression of MHCI and epithelial markers and increased PD-L1 expression. D, E Immunological dormancy, metabolic switch, and activation of metastasis-associated kinases promote disseminating cells to metastasize to different organs having a pre-metastatic niche for the initiation of metastasis (PMN in the liver is illustrated in the figure). F Several factors, including exosomes, miRs, and immune cell secreted factors, such as MIF, cytokines, and various chemokines, guide the development of PMN. G, H Hepatic stellate cells and Kupffer cells initiate fibrosis at the early stages of PMN development, and different chemokines, MMPs, and cytokines facilitate adaptation of tumor cells to the PMN. I Liver metastasis with different immune cells and metastasis-associated fibroblasts and resident hepatic cells. Abbreviations: PMN- pre-metastatic niche; MHC- major histocompatibility complex; EMT- epithelial to mesenchymal transition; PD-L1- programmed death receptor ligand-1; MIF- macrophage migration inhibitory factor; miR- micro-RNA; ncRNA- non-coding RNA; TGFβ- tumor growth factor- β; IL- interleukin; MMP- matrix metalloprotease

Fig. 2

Factors contributing to immunosuppression and PDAC metastasis. A Downregulation of AMPK, a metabolic sensor, decreases several metabolic enzymes leading to reduced glucose and ATP levels in the tumor, which triggers cells to undergo EMT. B Metabolic priming and lactate accumulation promote the infiltration of suppressive immune cells that contribute to an immunosuppressive cytokine and chemokine pool and deregulate immune surveillance, Ag-presentation, and effector immune functions. Immune dysregulation and increased immunosuppression promote EMT and metastasis in PDAC. Abbreviations: Arg1-arginase 1; MAM-metastasis-associated macrophages MRC1- mannose receptor C-type 1, TAMs- tumor associated macrophages; MDSCs- myeloid-derived suppressor cells; Treg- regulatory T cells; NK cells- natural killer cells; HSF1- heat shock factor -1; mTOR- mammalian target of rapamycin; PKM2- pyruvate kinase M2

Fig. 3

Metabolic alterations regulate immunosuppression in metastatic PDAC. The metabolic microenvironment in pancreatic tumors changes with disease progression. A, B Altered Trp catabolism due to upregulated IDO1 result in high kynurenine levels which activates AhR to promote enrichment of Tregs and M2-TAMs, resulting in  enhanced immunosuppression in the TME. C, D Metabolic byproducts and high levels of non-essential AA (serine/arginine) and extracellular methionine enhance immunosuppression in PDAC tumors. E, F Increased immunosuppression is associated with immune dysfunction, immune evasion, and metastasis. Abbreviations: Trp- tryptophan; AhR-aryl hydrocarbon receptor; IDO1- indoleamine 2, 3-dioxygenase 1; ExNEAA- extracellular non-essential amino acid; PD1- programmed cell death receptor 1; CTLA4- cytotoxic T-lymphocyte antigen-4; iNOS- inducible nitric oxide synthase; Met- methionine; Ser- serine; Arg- arginine; SAM- S-adenosyl methionine