Tumor‐infiltrating dendritic cells exhibit defective cross‐presentation of tumor antigens, but is reversed by chemotherapy

Abstract

Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8+ T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b + DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC crosspresentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.Keywords: Chemotherapy r Cross-presentation r Gemcitabine r T-cell activation r Tumor-infiltrating dendritic cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTumor Ags derived from solid tumors can be presented by host APCs to naïve CD8 + T cells in a process known as McDonnell et al. Eur. J. Immunol. 2015. 45: 49-59 role of DCs in the cross-priming of tumor-specific T-cell responses [3][4][5][6][7]. Furthermore, the most effective antitumor immunotherapies are associated with improving the response to cross-presented Ags [1,2]. When studying how DCs cross-present tumor Ags, most attention has focused on the priming events occurring in the tumordraining lymph node (TDLN). However, there is evidence that DC cross-presentation within tissues is also an important component of memory and even naïve CD8+ T-cell responses [8,9]. Additionally, it has been shown that tumor-infiltrating DCs (TiDCs) may be functionally impaired and/or unable to migrate to TDLNs [10].In this study, we examined the capacity of TiDCs to crosspresent cell-associated tumor Ag using the murine malignant mesothelioma line, AB1-HA, where influenza virus HA is a membrane-bound tumor neo-Ag. We characterized TiDCs in terms of their phenotype, Ag uptake, and cross-presenting capacity during normal tumor growth and during regression following systemic cytotoxic chemotherapy with gemcitabine. ResultsTumor Ag-specific T-cell activation does not occur in the tumor microenvironment In order to determine if tumor-specific CD8+ T cells recognize Ag presented in the tumor environment, we directly injected CFSElabeled, HA-specific (CL4) T...

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