1 Characterization of surface markers expressed on spleen DCs from tumor-bearing -MYC mice that did or did not receive ICB treatment

1 Characterization of surface markers expressed on spleen DCs from tumor-bearing -MYC mice that did or did not receive ICB treatment. consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses. Electronic supplementary material The online version of this article (10.1007/s00262-020-02767-6) contains supplementary material, which is available to authorized users. test or MannCWhitney test. All results were expressed as means??SEM. Data analysis was performed with Prism 5.0 software (GraphPad). Results Increased expression of costimulatory molecules on TIDCs after ICB -MYC mice, which are of C57BL/6 origin, constitutively express a transgenic oncogene in a B-cell-specific manner, which leads to the development of endogenous B-cell lymphomas in 100% of mice [11]. Tumors grow in spleen and lymph nodes and lead to death between about day 70 and day ND-646 140 after birth. As shown earlier, DCs in the tumor microenvironment show phenotypic and functional alterations such as a reduced IL-12/IL-10 ratio and an impaired capability of stimulating T cells, although the expression of costimulatory molecules was increased [24]. Furthermore, the fraction of CD11clow DCs, which are considered as a T-cell-inhibiting DC subset ND-646 [28], was increased in comparison to the CD11chigh population. We furthermore showed that combined treatment with anti-PD-1 and anti-CTLA-4 mAbs significantly delays tumor development and even gives rise to long-time survivors, while therapy with single mAbs remains uneffective [13]. The frequencies of T lymphocytes, which are greatly diminished in the tumors, partly recover by ICB therapy [12]. While in diseased animals, the organ architecture is destroyed, lymphoid organs from ICB-treated mice, which are still healthy, show a normal distribution of T and B cells [13]. The therapeutic effect was associated with increased IFN- release by T cells as well as by NK cells [12]. To elucidate the impact of ICB on DCs, we phenotypically characterized spleen-derived TIDCs from mice that received ICB therapy and therefore showed delayed tumor growth. The comparison with untreated animals, whose tumor burdens were identical but only appeared at earlier time points than in the treated ND-646 group, revealed that ICB significantly reduced the ratio of CD11clow to CD11chigh cells (Fig.?1a, b). As the costimulatory molecules CD80 and CD86 expressed on DCs, which are most important for activating specific T cells and preventing T-cell anergization, can be upregulated by IFN- [24], we particularly analyzed these molecules on TIDCs. It turned out that ICB further increased the expression of CD80 and CD86, at least in the CD11clow subset (Fig.?1c, d). With regard to other maturation-associated markers, ICB showed variable effects. While slight increases were detected for CD40 and MHC class II, CD83 was markedly reduced after ICB, a finding that cannot be explained for the time being (Supplementary Fig. 1). Of notice, PD-L1, which interacts with PD-1 and therefore impairs T-cell functions, ND-646 was significantly reduced on CD11clow TIDCs from ICB-treated mice. Open in a separate windowpane Fig. 1 Characterization of surface markers indicated on spleen DCs from tumor-bearing -MYC mice that did or did not receive ICB treatment. a Distribution of CD11clow and CD11chigh DCs. In the example demonstrated, the ratio CD11clow/CD11chigh is definitely 5.12 (untreated) and 2.87 (treated). b Compilation of CD11clow/CD11chigh ratios from untreated ((70112332, 70112337, 110662 and 110664), (2012.056.3) and (SFB-TR 156 and DFG Ro 764/15-2). Author contribution A.S., F.A., V.B. and T.R. performed experiments and analyzed data, A.S. contributed to writing the manuscript and drafted the numbers, M.R. and R.M. conceived and supervised the study, R.M. published the manuscript. All authors agreed to the content and the submission of the manuscript. Funding Open Access funding enabled and structured by Projekt ND-646 DEAL. Rabbit Polyclonal to RFX2 The work was supported by grants from (70112332, 70112337, 110662, and 110664), (2012.056.3) and (SFB-TR 156 and DFG Ro 764/15-2). Compliance with honest requirements Discord of interestThe authors declare that they have no conflicts of interest. Ethics approvalAnimal experiments were authorized by the responsible expert. Footnotes Publisher’s Notice Springer Nature remains neutral with regard to jurisdictional statements in published maps and institutional affiliations..