Immunotherapy for pancreatic cancer: Barriers and breakthroughs

Abstract

Immunotherapy is a rapidly growing field and represents a paradigm shift in the treatment of malignancies as it offers a new therapeutic approach beyond surgery, conventional chemotherapy, and radiation treatment. Targeting immune checkpoints, such as cytotoxic T‐lymphocyte‐associated antigen 4 and programmed death 1/programmed death ligand 1 has had immense clinical success resulting in sustained treatment response for a subset of patients with certain malignancies such as melanoma, non‐small‐cell lung cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, renal cell cancer, hepatocellular cancer, and metastatic colorectal cancer. Importantly, there has been limited success in the use of immunotherapy in the treatment of pancreatic cancer. Investigation into the complex tumor microenvironment of pancreatic cancer that is composed of immune cells, stromal cells, and extracellular matrix proteins has begun to shed light on important attributes of this microenvironment that act as barriers to the effective use of immunotherapy. In this review, we will discuss the progress that has been made in treating pancreatic cancer with immunotherapy, the barriers that have limited treatment success, and breakthroughs with combination treatments that hold promise for the future.

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…The "cold" nature of these tumors, as well as the abundance and complexity of their TME, may explain the lack of effectiveness of conventional immunotherapy treatments. Thus, combinatorial strategies targeting the immune system (e.g., PD-L1) and molecular inductors of pancreatic TME complexity (e.g., colony stimulating factor receptor 1(CSFR1), chemokine C-X-C receptor 4 (CXCR4)) are in clinical trials, and it is expected that the reprograming of the TME will improve the benefit of classical immunotherapy treatment [41].…”

Effect of the CXCR4 antagonist plerixafor on endogenous neutrophil dynamics in the bone marrow, lung and spleen

“…Recently it was shown that chronic administration of plerixafor is a feasible strategy for long‐term treatment of WHIM patients, reducing infection frequency and wart burden associated with the disease 17 . Chronic treatment with plerixafor is also being considered for additional clinical applications including pulmonary fibrosis, pancreatic cancer (Camplex‐1 trial), and leukemia, where the mechanism of action appears independent of the effect of plerixafor on neutrophil dynamics 18–20 . However if plerixafor affects neutrophil dynamics in the lung, it has the potential to compromise lung host defense and this may have a detrimental impact on these patients especially if otherwise immunocompromised.…”

Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling

“…Focal adhesion kinase activity drives induction of an immunosuppressive TME Analyses of patient pancreatic tumor tissue have shown that T cells can infiltrate pancreatic lesions and furthermore, in line with observations made in other cancer types, T cell infiltration also correlates with response to checkpoint blockade therapy in pancreatic ductal adenocarcinoma (PDAC; Torphy et al, 2018). Previous studies using GEMMs to model PDAC have characterized the resulting tumors as containing densely fibrotic stroma and immunosuppressive immune cell populations, namely, tumor-associated macrophages (TAM), MDSC, and Treg cells (Clark et al, 2007;Feig et al, 2012;Jiang et al, 2016).…”