Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses.

Rohan Diwanji, Neil A O'Brien, Jiyoung E Choi, Beverly Nguyen, Tyler Laszewski, Angelo L Grauel, Zheng Yan, Xin Xu, Jincheng Wu, David A Ruddy, Michelle Piquet, Marc R Pelletier, Alexander Savchenko, LaSalette Charette, Vanessa Rodrik-Outmezguine, Jason Baum, John M Millholland, Connie C Wong, Anne-Marie Martin, Glenn Dranoff, Iulian Pruteanu-Malinici, Viviana Cremasco, Catherine Sabatos-Peyton, Pushpa Jayaraman

High levels of IL-1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL-1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL-1β blockade induced by the monoclonal antibodies canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-PD-1, anti-VEGFα and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL-1β blockade enhanced the effectiveness of docetaxel and anti-PD-1. Accompanying these effects, blockade of IL-1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAFs) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL-1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL-1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL-1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages and lines of treatment.