The tumor immune microenvironment in pancreatic cancer and its potential in the identification of immunotherapy biomarkers

ABSTRACT

Introduction

Pancreatic cancer (PC) has an extremely poor prognosis, even with surgical resection and triplet chemotherapy treatment. Cancer immunotherapy has been recently approved for tumor-agnostic treatment with genome analysis, including in PC. However, it has limited efficacy.

Areas covered

In addition to the low tumor mutation burden, one of the difficulties of immunotherapy in PC is the presence of abundant stromal cells in its microenvironment. Among stromal cells, cancer-associated fibroblasts (CAFs) play a major role in immunotherapy resistance, and CAF-targeted therapies are currently under development, including those in combination with immunotherapies. Meanwhile, microbiomes and tumor-derived exosomes (TDEs) have been shown to alter the behavior of distant receptor cells in PC. This review discusses the role of CAFs, microbiomes, and TDEs in PC tumor immunity.

Expert opinion

Elucidating the mechanisms by which CAFs, microbiomes, and TDEs are involved in the tumorigenesis of PC will be helpful for developing novel immunotherapeutic strategies and identifying companion biomarkers for immunotherapy. Spatial single-cell analysis of the tumor microenvironment will be useful for identifying biomarkers of PC immunity. Furthermore, given the complexity of immune mechanisms, artificial intelligence models will be beneficial for predicting the efficacy of immunotherapy.

KEYWORDS:

• Cancer-associated fibroblast
• exosome
• immunotherapy
• microbiome
• pancreatic cancer

Article highlights

• Cancer-associated fibroblasts (CAFs), microbiomes, and tumor-derived exosomes (TDEs) have been suggested as candidate biomarkers monitoring the response to pancreatic cancer immunotherapy.

• CAFs, microbiomes, and TDEs can be identified as factors that can functionally alter the tumor immune microenvironment (TIME).

• Several clinical trials of treatments targeting CAFs in combination with immune checkpoint inhibitors in patients with pancreatic cancer are underway.

• The involvement of oral, intestinal, and intratumoral microbiomes in tumor immunity has been shown.

• TDEs express immune-related molecules such as PD-L1 and MICA/B, resulting in an immunosuppressive TIME.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.