The complex role of IL-6 signalling in chemo-immunotherapy
Elham Beyranvand Nejad1, Camilla Labrie1, Suzanne van Duikeren2, Thorbald van Hall1, Ramon Arens2 and Sjoerd H. van der Burg1
1Department of Medical Oncology, 2Department of Immunohematology and Blood Transfusion, LUMC, Leiden, the Netherlands
IL-6 is pleiotropic cytokine which mediates multiple immune inflammatory responses. Deregulation of this cytokine contributes to pathogenesis of a variety of inflammatory diseases, including cancer. Its overexpression in many cancer types associates with resistance to chemotherapy. However, the underlying mechanism of this resistance is largely unknown. Here, first we investigated if production of IL-6 in a preclinical mouse model of HPV16-induced cancer can curtail the antitumor effect of chemo-immunotherapy. Although, overexpression of IL-6 did no mediate resistance to chemotherapy in vitro, it severely hampered the antitumor effects of chemotherapy and immunotherapy in the mouse model. A comprehensive immune analysis showed a decreased percentage of intratumoral leukocytes and a higher influx of myeloid cells, in particular immature inflammatory myeloid cells both in tumor and spleen of IL-6-producing tumor bearing mice. These data suggested that the resistance to therapy of IL-6 producing tumor cells is mediated by changes in the local and systemic myeloid cell composition. Mice were then treated with a blocking IL-6R antibody and this normalized the immune infiltration under steady state conditions. Surprisingly, when the IL-6R blocking antibody was administered during immunotherapy, the antitumor effect was not improved but in fact deteriorated. These data suggest that there are more parameters that need to be considered for the design of a combination therapy that focuses on IL-6 pathway targeting with immunotherapy. We are currently studying the mechanisms underlying the decreased clinical efficacy of the combination approach.
This study is funded by Dutch Cancer Society.