Williford and Ishihara et al. showed enhanced CCL4 levels and stroma localization in tumors when mice received CCL4 fused to a collagen-binding domain (CBD). CCL4-CBD synergized with checkpoint inhibitors (CPI) to slow tumor growth in a spontaneously developing and in multiple implanted CPI-poorly responsive cancer mouse models, and to establish memory. IHC and flow cytometry of tumor infiltrates revealed that these effects correlated with CD103+ DC and CD8+ T cells (eliminated in Batf3-/- mice). CXCR3 blockade eliminated the therapeutic benefit, showing that CCL4-CBD recruited CD103+ DC and CD8+ T cells that make IFNγ and TNFα to mediate efficacy.
Contributed by Paula Hochman
Although a clinical breakthrough for cancer treatment, it remains that a minority of patients respond to checkpoint inhibitor (CPI) immunotherapy. The composition of tumor-infiltrating immune cells has been identified as a key factor influencing CPI therapy success. Thus, enhancing tumor immune cell infiltration is a critical challenge. A lack of the chemokine CCL4 within the tumor microenvironment leads to the absence of CD103+ dendritic cells (DCs), a crucial cell population influencing CPI responsiveness. Here, we use a tumor stroma–targeting approach to deliver CCL4; by generating a fusion protein of CCL4 and the collagen-binding domain (CBD) of von Willebrand factor, we show that CBD fusion enhances CCL4 tumor localization. Intravenous CBD-CCL4 administration recruits CD103+ DCs and CD8+ T cells and improves the antitumor effect of CPI immunotherapy in multiple tumor models, including poor responders to CPI. Thus, CBD-CCL4 holds clinical translational potential by enhancing efficacy of CPI immunotherapy.
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637 USA (2) Committee on Immunology, University of Chicago, Chicago IL 60637 USA (3) Institute of
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637 USA (2) Committee on Immunology, University of Chicago, Chicago IL 60637 USA (3) Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland (4) Ben May Department for Cancer Research, University of Chicago, Chicago IL 60637 USA.
