Sunitinib depletes myeloid-derived suppressor cells and synergizes with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication

Abstract

The high efficacy of therapeutic cancer vaccines in preclinical studies has yet to be fully achieved in clinical trials. Tumor immune suppression is a critical factor that hampers the desired antitumor effect. Here, we analyzed the combined effect of a cancer vaccine and the receptor tyrosine kinase inhibitor sunitinib. Sunitinib was administered intraperitoneally, alone or in combination with intramuscular immunization using a viral vector based cancer vaccine composed of Semliki Forest virus replicon particles and encoding the oncoproteins E6 and E7 (SFVeE6,7) of human papilloma virus (HPV). We first demonstrated that treatment of tumor-bearing mice with sunitinib alone dose-dependently depleted myeloid-derived suppressor cells (MDSCs) in the tumor, spleen and in circulation. Concomitantly, the number of CD8+ T cells increased 2–fold and, on the basis of CD69 expression, their activation status was greatly enhanced. The intrinsic immunosuppressive activity of residual MDSCs after sunitinib treatment was not changed in a dose-dependent fashion. We next combined sunitinib treatment with SFVeE6,7 immunization. This combined treatment resulted in a 1.5- and 3-fold increase of E7-specific cytotoxic T lymphocytes (CTLs) present within the circulation and tumor, respectively, as compared to immunization only. The ratio of E7-specific CTLs to MDSCs in blood thereby increased 10- to 20-fold and in tumors up to 12.5-fold. As a result, the combined treatment strongly enhanced the antitumor effect of the cancer vaccine. This study demonstrates that sunitinib creates a favorable microenvironment depleted of MDSCs and acts synergistically with a cancer vaccine resulting in enhanced levels of active tumor-antigen specific CTLs, thus changing the balance in favor of antitumor immunity.

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

“…Immunosuppression appears to be downregulated in mRCC patients treated with sunitinib or axitinib, whose Treg and MDSC cell populations are affected. Sorafenib has the opposite effect by reducing antigenspecific T-cell induction in vitro (6)(7)(8)(9)(10)(11). The different selectivities and affinities of the various drugs are thought to account for the diverse effects on myelopoiesis and immune cells (12).…”

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

“…Moreover, sunitinib responders showed decreased T-reg population and sunitinib synergized with radiotherapy improving patient progression-free survival [150]. Administration of sunitinib in combination with immunotherapy (a viral vector based cancer vaccine) with or without irradiation could further increase its antitumoral activity via depleting circulating and intra-tumoral MDSCs and elevation of the level of antigen specific cytotoxic T lymphocytes in mice [151,152] (Table 2). …”

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

“…Sunitinib, currently used in cancer therapy, depletes MDSCs and synergized with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication in mice (125). Similarly, dasatinib exhibits modest single-agent clinical efficacy but showed superior efficacy associated with reduced levels of MDSC and Treg populations in a combination treatment regimen with a DC vaccine candidate in a murine melanoma model (126).…”