A Decrease of Regulatory T Cells Correlates With Overall Survival After Sunitinib-based Antiangiogenic Therapy in Metastatic Renal Cancer Patients

Abstract

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…The role of VEGF in the expansion of Tregs within the tumor microenvironment may explain the observation that some antiangiogenic molecules decrease the number of both circularing and intratumoral Tregs in cancer patients [73][74][75][76]. Intriguingly, although all these antiangiogenic molecules efficiently inhibit the VEGF/VEGFR axis, sunitinib appears to be more potent at decreasing the number of Tregs than many other agents including sorafenib, whose Tregmodulatory potential remains matter of debate [75,[77][78][79][80].…”

The Immune Microenvironment of Human Tumors: General Significance and Clinical Impact

“…Indeed, innovative therapies that induce longer survival in patients modify the immune contexture of the tumors, usually by inducing an increased infiltration of CD8+ T cells [14,41]. It is the case for classical chemo- (53,54] and radio-therapies, for targeted therapies such as Braf inhibitors [55], or inhibitors of angiogenesis which decrease Treg and Myeloid-Derived Suppressor cells [56,57] and of course for immuno-modulatory antibodies such as anti-CTLA-4 [22], anti-PD1 [58] and anti-PD-L1 [59] (reviewed in ref 14 and in 25).…”

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma

“…OS was significantly longer in patients with a decrease in Treg after two or three cycles of sunitinib (p < 0.05). 81 Treg depletion has also been observed with axitinib. 83 In murine models, combining anti-angiogenic agents with immunotherapy enhanced the effectiveness of immunostimulation.…”

“…Some induce a less immunosuppressive tumor microenvironment by decreasing Tregs and MDSCs. 81 However, it is unclear whether they affect VEGF-dependent DC maturation or Treg proliferation. 82 In a prospective study of 28 mRCC patients receiving first-line sunitinib, the number of Tregs (defined as CD3CCD4CCD25(hi) Foxp3C) in blood and tumor fell after each sunitinib cycle.…”