Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

Abstract

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic “cold” tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the “defects” in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects.

GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

“…Such an approach with pancreatic adenocarcinoma tumours from mice has provided novel information regarding CAFs and cancer stem cells (Elyada et al, 2019; Lytle et al, 2019). In particular, since immune‐oncology therapeutic approaches for pancreatic adenocarcinoma have not been successful (Upadhrasta & Zheng, 2019), such efforts in tumour immune cells might reveal GPCRs that could be useful targets for such approaches.…”

“…Pancreatic adenocarcinoma tumour cells and the extracellular matrix/stromal cells in the microenvironment are potential targets for the treatment of pancreatic adenocarcinoma. Immuno‐oncology approaches that have improved the outcome of other cancers have not been successful for pancreatic adenocarcinoma, a “cold (non‐T‐cell inflamed) cancer” (Upadhrasta & Zheng, 2019).…”

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment

“…Stromal cells nurture the tumor through signaling molecules, chemokines and growth factors, to promote growth and reduce tumor vasculature, which further inhibits efficient drug delivery [3]. Stromal cells in the extracellular matrix can make up to 80% of the tumor mass and include myofibroblasts, cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs), and myeloid-derived suppressor cells [5,19]. The production of signaling molecules by stromal cells attracts additional stromal cells to the tumor, resulting in a positive feedback loop that ultimately leads to more inflammation and exclusion of effector T-cells from the tumor.…”

“…Pancreatic duct adenocarcinoma (PDAC) is a devastating disease with a 5-year survival in the US of just 10% and a projection to become one of the top leading causes of cancer-related deaths by 2030 [1,2]. Pancreatic cancer is characterized by rapid growth and invasiveness, and therapeutic targeting is complicated by multiple facets of the tumor microenvironment, including desmoplastic reaction, immunosuppression, and complex metabolic interactions [3][4][5]. The dense, surrounding stroma contains cells that produce growth factors to feed the tumor and block drug delivery [3].…”

“…The dense, surrounding stroma contains cells that produce growth factors to feed the tumor and block drug delivery [3]. The stroma also reduces cytotoxic T-cell infiltration to the tumor and suppresses T-cell activity that is present at the tumor [5]. Additionally, rapid metabolism of active drugs in the body decreases effective killing of pancreatic tumors [4].…”