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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4 + T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-γ production by activated CD4 + T cells. Additionally, IFN-γ stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4 + T cells and elicited systemic changes in T-helper subsets. 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.

IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction

“…In these experiments, we used a suboptimal dose of anti-CTLA4 and anti-PD-1 antibody so we might measure the additive effect of all therapeutic factors. Improvement of ICB treatment in the context of IL-6 blockade [18][19][20]28] and the detrimental effect of IL-6 in response to ICB has previously been described [29] , as well as the additive effect of SMG1 inhibition with ICB treatment (Fig. S3I).…”

Uncoupling Therapeutic Efficacy from Immune-Related Adverse Events in Immune Checkpoint Blockade

“…Tocilizumab is useful for dealing with adverse events secondary to other types of immunotherapy ( Kotch et al., 2019 ). Preclinical data have found that combined blockade of IL-6R and CTLA-4 enhances the antitumor responses in murine pancreatic tumor models, indicating that IL-6R blockade in combination with ICIs in the clinical settings have the potential to augment efficacy and limit irAEs ( Ware et al., 2019 , Ware et al, 2020 ). Mycophenolate mofetil is a purine antagonist that inhibits lymphocyte proliferation and is used as a second-line immunosuppressive drug ( Brahmer et al., 2018 ).…”