Fruquintinib saddles tumor immune tolerance by curbing pro-tumoral immature myeloid cell populations.

[INTRODUCTION] Myeloid-derived cells, particularly immature populations and tumor-associated macrophages, play a pivotal role in establishing immune tolerance and suppressing antitumor responses, thereby promoting cancer progression. Macrophage-derived lymphatic endothelial cell progenitors (M-LECP) are a population of VEGFR3/FLT4/CD310bone marrow-derived myeloid precursors that contribute to tumor lymphangiogenesis, metastases, and resistance to chemotherapy through activation of TLR receptors. In this context, we investigated the effects of fruquintinib, a selective oral VEGFR3/FLT4/CD310 inhibitor with high affinity for VEGFR3/FLT4/CD310, on tumor growth and size on colorectal (MC38, CT26) and breast (4T1, E0771) tumors. We next focused on its capacity to reshape the myeloid immune compartment in the syngeneic MC38 murine colorectal cancer model.

[RESULTS] Fruquintinib treatment significantly inhibited primary tumor growth, angiogenesis, and metastases in murine models of breast (4T1 and E0771) and colorectal (CT26 and MC38) cancer, respectively. Importantly, treatment with fruquintinib remodeled the tumor immune microenvironment of MC38 tumors by increasing the percentages of CD4 and CD8 T cells and selectively reducing myeloid cells, particularly CD11b populations of tumor-associated macrophages (TAMs) and type 2 dendritic cells. Notably, we observed similar effects in the bone marrow. In addition, treatment with fruquintinib reduced the population of bone marrow M-LECP, indicating a systemic impact. differentiation of macrophage-derived lymphatic endothelial cell precursors (M-LECP) from bone marrow cells was inhibited by fruquintinib and shifted towards pro-inflammatory phenotypes secreting IL-6, Il-1β, and less IL-10. Moreover, fruquintinib improved tumor responses to nab-paclitaxel and inhibited nab-paclitaxel-induced differentiation of M-LECP. Finally, analysis of VEGFR3/FLT4/CD310 expression in samples from cancer patients revealed higher expression of VEGFR3/FLT4/CD310 in metastatic tumors, as well as an association between VEGFR3/FLT4/CD310 expression and poorer patient survival.

[CONCLUSION] Overall, our findings offer new insights into the contribution of VEGFR3/FLT4/CD310 inhibition to restoring a pro-inflammatory tumor myeloid compartment and suggest M-LECP cells as candidate fruquintinib targets to overcome immunosuppression in tumors.