Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.

Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

“…Although immunotherapy has revolutionized the treatment of numerous types of cancer, there is no definitively positive result for PDAC patients 21 . PDAC is relatively resistant to chemotherapy or immunotherapy, mainly due to its characteristic TME with a fibrotic barrier formed by collagen, fibronectin, and hyaluronic acid, which prevents the delivery of sufficient chemodrugs and infiltration of immune effector cells 22 . The lack of NK and CD8 + T cells within the TME illustrates PDAC as a ‘cold’ tumour 11,12 .…”

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

“…Tumor-associated macrophages Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the pancreatic tumor stroma due in part to recruitment by oncogenic KRAS [163]. Either via direct tumorsignaling or via tumor-CAF crosstalk, TAMs are generally polarized to the immunosuppressive phenotype (M2) defined by Csf1R, CD206, and IL-10 expression along with reduced expression of MHC class II and Ly6C [155,164]. These M2 TAMs support tumorigenesis, immune escape (e.g., promoting Th2 cell differentiation), metastasis, and chemotherapeutic resistance [165].…”

Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma

“…The recruited and activated MAPK signalling pathway elements lead to the inflammation, apoptosis, proliferation, and carcinogenesis of pancreatic cells [ 39 ]. Increasing evidence has revealed that the infiltration and preferential accumulation of tumour antigen-specific T cells in PAAD are crucial to PAAD cell clearance and long-term remission [ 40 ].…”