Evaluation of methods to increase the expression of cytokine-induced killer cell chemoattractant cytokines in pancreatic cancer.

Adoptive Cell Therapies based on cytokine-induced killer cells (CIKs) can address the heterogeneity of solid tumors due to their multiple mechanisms of cancer cell recognition. However, tumor trafficking is one of the main limitations. In this work, we describe that a high proportion of CIKs obtained from pancreatic ductal adenocarcinoma patients express the CXCR3 and CCR5 receptors, and they migrate towards their corresponding chemokines CXCL10 and CCL5 in vitro. Using an immune competent orthotopic PDAC mouse model, we have investigated the ability of different clinically compatible interventions to increase the expression of these chemokines. No significant elevation was obtained with chemotherapy (5-fluorouracil, irinotecan, oxaliplatin, paclitaxel, gemcitabine or temozolomide), tyrosine kinase inhibitors sorafenib and sunitinib, or the immunostimulatory agents polyinosinic:polycytidylic acid, Mycobacterium tuberculosis antigens and diphtheria/pertussis/tetanus vaccine. In contrast, CXCL10 and CCL5 expression was stimulated by local administration of an adenoviral vector equipped with a drug-inducible expression system for interleukin-12 (IL-12). Combination of the vector and CIKs obtained a strong antitumor effect in the PDAC model, although it was mainly due to vector-mediated recruitment of endogenous immune cells. We conclude that additional barriers beyond chemokine expression should be overcome in order to unleash the full potential of CIKs on solid tumors.