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.