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

Ware, M. B.; McQuinn, C.; Zaidi, M. Y.; Knochelmann, H.; Mace, T. A.; Chen, Z.; Zhang, C.; Farren, M. R.; Ruggieri, A. N.; Bowers, J.; Shakya, R.; Farris, A. B.; Young, G.; Carson, W. E.; El-Rayes, B.; Paulos, C. M.; Lesinski, G. B.

doi:10.1101/2020.02.07.939199

bioRxiv · 10.1101/2020.02.07.939199

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

Ware, M. B.·McQuinn, C.·Zaidi, M. Y.·Knochelmann, H.·Mace, T. A.·Chen, Z.·Zhang, C.·Farren, M. R.·Ruggieri, A. N.·Bowers, J.·Shakya, R.·Farris, A. B.·Young, G.·Carson, W. E.·El-Rayes, B.·Paulos, C. M.·Lesinski, G. B.

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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-{gamma} production by activated CD4+ T cells. Additionally, IFN-{gamma} 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. One Sentence SummaryBlockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+ T cell and CXCR3-dependent manner.

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Ware, M. B., McQuinn, C., Zaidi, M. Y., Knochelmann, H., Mace, T. A., Chen, Z., Zhang, C., Farren, M. R., Ruggieri, A. N., Bowers, J., Shakya, R., Farris, A. B., Young, G., Carson, W. E., El-Rayes, B., Paulos, C. M., Lesinski, G. B.. 2020-02-07. Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T cell-dependent manner.. https://doi.org/10.1101/2020.02.07.939199

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