Different immunological effects of the molecular targeted agents sunitinib, everolimus and temsirolimus in patients with renal cell carcinoma

Treatment with molecular targeted agents together with immune checkpoint inhibitors will most likely improve the efficacy of current cancer immunotherapy. Because molecular targeted agents not only directly affect cancer cells, but also influence immune cells and modulate the tumor microenvironment, a better understanding of the overall immunological effects of these drugs will contribute to the rational design of combination therapies. Therefore, this study performed extensive immune monitoring of patients' peripheral blood mononuclear cells (PBMCs) to investigate the immunological effects of the molecular targeted agents sunitinib, everolimus and temsirolimus, which have been widely used for the treatment of renal cell carcinoma (RCC). Immunophenotyping and functional analysis of PBMCs revealed that these molecular targeted agents exerted different immunological effects on patients with RCC. Sunitinib decreased the percentage of early-stage myeloid-derived suppressor cells (eMDSCs) and increased natural killer cells, but did not affect the phenotypes and effector functions of CD4(+) or CD8(+) T cells. Everolimus decreased effector regulatory T cells, but also decreased IL-2-producing CD4(+) T cells and increased dysfunctional CD8(+) T cells. Conversely, temsirolimus decreased programmed cell death protein 1(+)CD8(+) T cells and eMDSCs, but increased interferon-gamma and tumor necrosis factor-alpha double producers at the same time as decreasing dysfunctional CD8(+) T cells, albeit not significantly. In conclusion, although everolimus and temsirolimus are mTOR inhibitors, their effects on overall T-cell functions are very different. Therefore, although it may increase the risk of immune-related toxicity, temsirolimus is expected to offer the best outcome when combined with other immunomodulators for the development of cancer immunotherapy.