Tumor-associated macrophage (TAM), occupying 50% weight of total tumor tissue, not only prevent T cell from attacking cancer cells, but also secrete cytokines to enhance angiogenesis in tumor microenvironment, and promote metastasis of malignant cells [1],[2].Targeting the growth of these cells, therefore, seemes like an appealing therapeutic option. However, application of CSF1R inhibitors that block the growth-promoting CSF1/CSF1R pathway in these cells were found to be of limited anti-tumor value when used as the sole therapeutic agent, but not when combined with other drugs, such as PD-L1.
In search of an explanation for this phenomenon, researchers at Stanford University were recently able to reveal a chemokine-dependent mechanism that could be exploited by combinatorial drugs to improve the efficiency of CSF1R inhibitors[4]. The basis of this mechanism lied at the recruitment of PMN-MDSCs to the tumor environment through chemokines secreted by carcinoma-associated fibroblasts (CAF). Interestingly, CSF1 produced by tumor cells caused an HDAC2-mediated down-regulation of the chemokine expression in CAFs, which limited the migration of PMN-MDSC to tumors. Therefore, treatment of cancer cells with CSF1R inhibitors disrupted this crosstalk and led to an increase in the recruitment and infiltration of tumor-promoting granulocytes to tumors, reducing the efficiency of CSF1R inhibitors.
Another part of this puzzle solved by Kumar et al. demonstrated the involvement of CXCR2 in this phenomenon. This molecule serves as the receptor for most chemokines upregulated by the CSF1R inhibitor. As a result, combinatorial treatment with both CSF1R and CXCR2 inhibitors was found to be effective in lowering both populations of TAMs and PMN-MDSCs in tumor sites to significantly reduce tumor growth. Moreover, addition of PD-1 antibody to the drug cocktail resulted in a dramatic anti-tumor effect; higher than when the PD-1 antibody was used alone. The discovery of this sophisticated regulatory network can now provide further opportunities for developing effective anti-cancer therapeutics targeting tumor microenvironment.
