Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T-cell-dependent manner.

Abstract This study aimed to enhance anti-tumor immune responses to pancreatic cancer via antibody-based blockade of interleukin-6 (IL-6) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Mice bearing subcutaneous MT5 or orthotopic KPC-luc pancreatic tumors were treated with antibodies to IL-6, CTLA-4, or the combination. This combination significantly inhibited tumor growth, accompanied by overwhelming T-cell infiltration. Tcell depletion studies unveiled a unique dependence on CD4+ T-cells for anti-tumor activity of this combination therapy. In vivo blockade of CXCR3 prevented orthotopic tumor regression in the presence of the combination treatment, demonstrating an integral role for the CXCR3 axis in mediating efficacy. Increased expression of CXCR3 on tumor infiltrating cells was observed by IHC and by PCR. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation.