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.
