Understanding the immune landscape and tumor microenvironment of pancreatic cancer to improve immunotherapy

Abstract

Immunotherapy has revolutionized cancer treatment for several hematologic and solid organ malignancies; however, pancreatic cancer remains unresponsive to conventional immunotherapies. Several characteristics of pancreatic cancer present challenges to successful treatment with immunotherapy, including its aggressive biology, poor immunogenicity, and abundant desmoplastic stroma which can impede effector T cell infiltration and promote an immunosuppressive microenvironment.In this review, we evaluate the current understanding of the immune and stromal landscapes of pancreatic cancer, discuss the successes and failures of stromatargeted therapies, and highlight how stroma-directed therapies may be synergistic with immunotherapy. K E Y W O R D S desmoplasia, immunotherapy, pancreatic ductal adenocarcinoma, stroma 1 | INTRODUCTION Cancer immunosurveillance is the concept that the immune system can identify and kill tumors and is based on the foundational principle that T cells can identify and kill cancer cells with unique or foreign antigens. 1 The concept of cancer immunosurveillance was further refined to the theory of cancer immunoediting based on the understanding that the immune system can act to protect a host from tumor development, but also is capable of promoting tumor growth. 2 The field of cancer immunotherapy focuses on unleashing the ability of the host's immune system to eliminate tumors through disrupting immunosuppressive signals with immune checkpoint blockade, enhancing tumor-specific T cell activity through adoptive T cell therapy, and improving antitumor T cell education with vaccines. Chimeric antigen receptor (CAR) T cell therapies are now successfully being used to treat several hematological malignancies. 3,4 Some solid organ malignancies are also now effectively being treated using immunotherapy as immune checkpoint blockade has revolutionized the field of immunotherapy over the past decade. 5,6Despite the success of immune checkpoint blockade in treating several solid organ malignancies, pancreatic cancer remains unresponsive to conventional immunotherapies. 7,8 Pancreatic ductal adenocarcinoma, which comprises well over 90% of pancreatic cancers and is estimated to be the third leading cause of cancer-related deaths in the United States in 2020 has several unique characteristics which present challenges to successful treatment with immunotherapy. 9 Pancreatic cancer often presents at a very late stage, with only 20% of the patients diagnosed with surgically resectable disease, which currently is the only potentially curative treatment. This late presentation, in conjunction with the aggressive biology of this disease, leads to patients often being diagnosed with metastatic disease and poor overall survival rates. 10 Secondly, pancreatic cancer is often described as an immunologically cold cancer with relatively few neoantigens to be recognized by immune cells.Lastly, pancreatic cancer has a characteristic desmoplastic stromal

m6A Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pancreatic Cancer

“…Mutated KRAS in pancreatic cancer plays a central role in tumor development and growth by regulating T-cell cytokines in TME. By acting on downstream effectors, KRAS leads to impaired T-cell recognition of tumor cells, which may mediate immunity escape ( 22 , 42 ). There are mutations of TP53 in most types of cancers.…”

“…Recent studies have shown that m 6 A methylation modification plays an indispensable role in a variety of immune-related biological processes, including innate and acquired immune response, immune recognition, immune cell dynamic balance, and anti-tumor immune response (22). Since most studies mainly focus on the regulatory relationship between single m 6 A regulator and immune cell type, the comprehensive landscape of TME immune-infiltrating mediated by multiple m 6 A regulators in PC has not been fully understood.…”

“…Increasing research focuses on whether the components of TME (including acellular matrix, pancreatic stellate cells, immune cells and soluble factors) can be used as effective targets for PC therapy ( 21 ). Recently, immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy have become popular immunotherapies related to TME in pancreatic cancer ( 22 , 23 ). However, whether these therapies can bring clinical benefits remains to be fully studied.…”

Identification of Prognostic Immune-Related Genes in Pancreatic Adenocarcinoma and Establishment of a Prognostic Nomogram: A Bioinformatic Study

“…Some studies have shown that the establishment of an "immune score" system for expressing pancreatic cancer could be used to assess the degree of immune cell infiltration in the tumor immune microenvironment [50]. Improving our understanding of how PAAD immune and stromal components interact and the tumor microenvironment can help improve our immunotherapy [51,52]. Future strategies using immunotherapy to treat pancreatic cancer include changing immune checkpoint inhibitors from monotherapy to combination therapy and combining immunotherapy with chemotherapy, radiation therapy, and targeted therapy [53].…”

A signature of 18 immune‐related gene pairs to predict the prognosis of pancreatic cancer patients

“…Due to its components of plentiful desmoplastic stroma which could handicap the infiltration of effector T-cell and further facilitate the immunosuppressive microenvironment, and the traits of poor immunogenicity, it was fairly intricate to accomplish immunotherapy into pancreatic cancer. 16 Despite it was a gigantic challenge, previous literatures have implied the role of immune system in PC and supplied the potential feasibility to accomplish this target. [7][8][9] As yet, the role of IRGs in PC is still unclear.…”