Modulating the tumor immune microenvironment with sunitinib malate supports the rationale for combined treatment with immunotherapy

Small molecule inhibitors have proven useful in the treatment of a variety of tumors, but they are often limited by unsustainable benefits and confer resistance quickly. Immunotherapy can result in durable clinical responses, but activity only occurs in a minority of patients. The unfavorable tumor microenvironment (TME) is an important factor limiting immunotherapy. An appropriate understanding of how small molecule inhibitors modulate the TME may optimize the combination of targeted treatment and immunotherapy in managing tumors. In this study, we found that transient treatment with sunitinib malate inhibited the disorganized extension of tumor vessels, pericytes and collagen IV but increased the relative ratio of pericyte-wrapping blood vessels with alleviated hypoxia in tumors, which resulted from tumor vascular normalization. Sunitinib malate increased infiltration of CD8+ T cells and decreased regulatory T cells (Tregs), accompanied by inhibited expression of TGF-β1 and IL-10 and increased CCL-28, IFN-γ and IL-12, but no significant inhibition of myeloid-derived suppressor cells (MDSCs) was observed. In addition, sunitinib malate increased the levels of PD-1 and PD-L1 in TME, combined with anti-PD-1 therapy showed a significant reduction in tumor burden compared with either monotherapy, suggesting that anti-PD-1 therapy is reasonable after sunitinib malate treatment.