Pancreatic cancer induces an immunosuppressive microenvironment. This feature is due to the presence in the stroma of cancer-associated fibroblasts (CAFs), myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), dendritic cells and tumor-infiltrating lymphocytes (TILs). Differently from other tumors (for instance, melanoma), the results of early clinical trials carried out in pancreatic cancer using antibodies against the immune « checkpoints » are controversial. Indeed, no positive response was observed with the anti-programmed cell death-ligand 1 (PD-L1) antibody, despite the correlation between PD-L1 expression in pancreatic cancer and poor prognosis. Indeed, binding of PD-L1 to programmed cell death 1 (PD-1), its receptor, inhibits lymphocyte T activation against cancer cells that secrete PDL-1. Nevertheless, results are expected from the association of the anti-PDL1 antibody with a CXCR4 inhibitor. CAFs secrete a CXCR4 ligand that induces an immunosuppressive response. Inhibition of this CAF activity using a CXCR4 inhibitor associated with an anti-PDL-1 antibody has shown encouraging effects on pancreatic tumor regression in mice.
Like for the anti- PD-L1 antibody, negative results were obtained also with another anti-immune checkpoint antibody (ipilimumab, an anti-CTLA4 antibody) in patients with advanced pancreatic cancer (phase II clinical trial). Conversely, induction of the anti-tumor immune response using a CD40 agonist (a member of the TNF receptor family expressed by TAMs), leading to macrophage accumulation in the tumor, seems to be an interesting alternative. Tumor regression was observed in a few patients with advanced pancreatic cancer who received this CD40 agonist in combination with gemcitabine as first-line treatment.
Interesting results were obtained with vaccines, such as GVAX, composed of transfected cancer cells that express the GM-CSF growth factor. GM-CSF has an immunostimulatory effect by attracting dendritic cells and activating lymphocytes T. Positive results on patient survival were obtained in a phase II clinical trial in which GVAX was associated with CRS-207 (attenuated Listeria monocytogenes bacteria that stimulate the innate or adaptive immune response through mesothelin expression). However, a strict patients’ selection is required. Its combination with anti-CTLA4 or anti-PDL-1 antibodies could also represent a promising strategy.