Immunotherapy and Pancreatic Cancer: A Lost Challenge?

Abstract

Although immunotherapy has proved to be a very efficient therapeutic strategy for many types of tumors, the results for pancreatic cancer (PC) have been very poor. Indeed, chemotherapy remains the standard treatment for this tumor in the advanced stage. Clinical data showed that only a small portion of PC patients with high microsatellite instability/mismatch repair deficiency benefit from immunotherapy. However, the low prevalence of these alterations was not sufficient to lead to a practice change in the treatment strategy of this tumor. The main reasons for the poor efficacy of immunotherapy probably lie in the peculiar features of the pancreatic tumor microenvironment in comparison with other malignancies. In addition, the biomarkers usually evaluated to define immunotherapy efficacy in other cancers appear to be useless in PC. This review aims to describe the main features of the pancreatic tumor microenvironment from an immunological point of view and to summarize the current data on immunotherapy efficacy and immune biomarkers in PC.

PD-1 blockade combined with gemcitabine plus nab-paclitaxel is superior to chemotherapy alone in the management of unresectable stage III/IV pancreatic cancer: a retrospective real-world study

“…ICI therapy relies on immune cells, and the low mutation burden of PC leads to the lack of infiltration of active immune cells in the TME ( 25 ). On the other hand, the components of the TME in PC, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and tumor-associated fibroblasts, collectively contribute to immunosuppression ( 26 ). Finally, the TME of PC possesses a dense connective tissue stroma ( 27 ), which results in low T cell infiltration in the TME ( 28 – 30 ).…”

Chimeric Antigen Receptor T Cell Therapy for Pancreatic Cancer: A Review of Current Evidence

“…As mentioned above, immunotherapy is effective in treating a variety of cancers; however, it is not associated with improved overall survival in PC patients. This could be explained by the specific TME, low tumor mutational burden, and, consequently, the low level of cancer neoantigens [ 22 ]. Another explanation may be the existence of different PD-1/PD-L1 or CTLA-4 immune checkpoints in PC.…”

Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer

“…It is a relatively new treatment option for pancreatic cancer and has shown promise in some cases. However, its efficacy in pancreatic cancer is highly limited by the peculiar features of the pancreatic tumor microenvironment compared to other malignancies [115]. Consequently, a combination of immunotherapy and targeted therapy designed to suppress the resistance of tumor microenvironment may be a fascinating treatment approach.…”