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Pancreatic Cancer and Immunotherapy: A Clinical Overview.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

SUBMITTER: Timmer FEF

PROVIDER: S-EPMC8393975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEmerging evidence has shown that intra-tumor immune features are associated with response to immune checkpoint blockade (ICB) therapy. Accordingly, patient stratification is needed for identifying target patients and designing strategies to improve the efficacy of ICB therapy. We aimed to depict the specific immune features of patients with pancreatic cancer and explore the implication of immune diversity in prognostic prediction and individualized immunotherapy.MethodsFrom transcriptional profiles of 383 tumor samples in TCGA, ICGC, and GEO database, robust immune subtypes which had different response immunotherapy, including ICB therapy, were identified by consensus clustering with five gene modules. DEGs analysis and tumor microarray were used to screen and demonstrate potential targets for improving ICB therapy.ResultsThree subtypes of pancreatic cancer, namely cluster 1-3 (C1-C3), characterized with distinct immune features and prognosis, were generated. Of that, subtype C1 was an immune-cold type in lack of immune regulators, subtype C2, with an immunosuppression-dominated phenotype characterized by robust TGF? signaling and stromal reaction, showed the worst prognosis, subtype C3 was an immune-hot type, with massive immune cell infiltration and in abundance of immune regulators. The disparity of immune features uncovered the discrepant applicability of anti-PD-1/PD-L1 therapy and potential sensitivity to other alternative immunotherapy for each subtype. Patients in C3 were more suitable for anti-PD-1/PD-L1 therapy, while patients in the other two clusters may need combined strategies targeted on other immune checkpoints or oncogenic pathways. A promising target for improving anti-PD-1/PD-L1 treatment, TGM2, was screened out and its role in the regulation of PD-L1 was investigated for the first time.ConclusionCollectively, immune features of pancreatic cancer contribute to distinct immunosuppressive mechanisms that are responsible for individualized immunotherapy. Despite pancreatic cancer being considered as a poor immunogenic cancer type, the derived immune subtypes may have implications in tailored designing of immunotherapy for the patients. TGM2 has potential synergistic roles with ICB therapy.

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Pancreatic Cancer and Immunotherapy: A Clinical Overview.

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