Emerging trends in the immunotherapy of pancreatic cancer

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 43,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating the patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC. Immunotherapy modulates the host's immune response to tumor-associated antigens (TAAs), eradicates cancer cells by reducing host tolerance to TAAs and provides both short- and long-term protection against the disease. Passive immunotherapies like monoclonal antibodies or engineered T-cell based therapies directly target tumor cells by recognizing TAAs. Active immunotherapies, like cancer vaccines, on the other hand elicit a long-lasting immune response via activation of the patient's immune cells against cancer cells. Several immunotherapy strategies have been tested for anti-tumor responses alone and in combination with standard care in multiple preclinical and clinical studies. In this review, we discuss various immunotherapy strategies used currently and their efficacy in abrogating self-antigen tolerance and immunosuppression, as well as their ability to eradicate PC.

B7‐H5/CD28H is a co‐stimulatory pathway and correlates with improved prognosis in pancreatic ductal adenocarcinoma

“…Considering the miserable prognosis of this disease, the identification of novel immunotherapeutic targets while taking into account the specific microenvironment of PDAC is of great importance and clinical interest . There is mounting evidence suggesting that immunotherapy, in conjunction with standard of care, can improve the outcomes of patients with pancreatic cancer . Many studies have assessed expressions of inhibitory receptors on exhausted CD8 + T cells, but without specific focus on co‐stimulatory molecules .…”

“…20 There is mounting evidence suggesting that immunotherapy, in conjunction with standard of care, can improve the outcomes of patients with pancreatic cancer. 21 Many studies have assessed expressions of inhibitory receptors on exhausted CD8 + T cells, but without specific focus on co-stimulatory molecules. 22 In this study, we demonstrate that B7-H5 can act as a co-stimulatory factor via its receptor, CD28H, which is expressed on T lymphocytes.…”

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

“…The mechanisms underlying the resistance of pancreatic cancer to the antitumor immune response have been extensively reviewed and are largely attributed to perturbations in immune surveillance, the process of immunoediting, and immune privilege [13,[59][60][61]. Although pancreatic cancer has been relatively resistant to singleagent checkpoint blockade when compared to more immune sensitive tumors, strategies for overcoming primary resistance to immunotherapy in pancreatic cancer are readily available from investigations in other solid tumor types focused on improving the antitumor efficacy of checkpoint blockade through combining various therapeutic modalities on a checkpoint inhibitor backbone [62][63][64].…”

Pancreatic Cancer, Gut Microbiota, and Therapeutic Efficacy

“…Great efforts have been made to solve this difficult problem. Gemcitabine-based combined therapies, tumor microenvironment (TME)-targeting strategies and immunotherapy are being developed to overcome drug resistance and ineffectiveness in PDAC [3].…”