Abstract
Tumor progression in the host leads to severe impairment of intrathymic T-cell differentiation/maturation, leading to the paralysis of cellular anti-tumor immunity. Such suppression manifests the erosion of CD4+CD8+ double-positive (DP) immature thymocytes and a gradual increase in CD4−CD8− double negative (DN) early T-cell progenitors. The impact of such changes on the T-cell progenitor pool in the context of cancer remains poorly investigated. Here, we show that tumor progression blocks the transition of Lin−Thy1.2+CD25+CD44+c-KitlowDN2b to Lin−Thy1.2+CD25+CD44−c-Kit−DN3 in T-cell maturation, instead leading to DN2-T-cell differentiation into dendritic cells (DC). We observed that thymic IL-10 expression is upregulated, particularly at cortico-medullary junctions (CMJ), under conditions of progressive disease, resulting in the termination of IL-10Rhigh DN2-T-cell maturation due to dysregulated expression of Notch1 and its target, CCR7 (thus restricting these cells to the CMJ). Intrathymic differentiation of T-cell precursors in IL-10−/− mice and in vitro fetal thymic organ cultures revealed that IL-10 promotes the interaction between thymic stromal cells and Notch1low DN2-T cells, thus facilitating these DN2-T cells to differentiate toward CD45+CD11c+MHC-II+ thymic DCs as a consequence of activating the Ikaros/IRF8 signaling axis. We conclude that a novel function of thymically-expressed IL-10 in the tumor-bearing host diverts T-cell differentiation toward a DC pathway, thus limiting the protective adaptive immune repertoire.
Highlights
Immune system decline, dysfunction, and senescence are commonly observed in the setting of cancer progression, with a pronounced restriction amongst CD8+ T effector cells, which are known for their capacity to mediate tumor regression [1]
Because T-cell development begins with CD4−CD8−double negative (DN) pro-T cells that subsequently pass through four well-defined maturation stages, we analyzed Lineage negative (Lin−)Thy1.2+DN subpopulations based on their differential expression of CD25 (IL-2Rβ), CD44, and CD117
In order to identify the exact stage of the blockade in DN-T-cell transition, we examined the status of the DN2a (CD25+CD44+c-Kithigh) and DN2b (CD25+CD44+c-Kitlow) subpopulations within the tumor-conditioned thymi
Summary
Dysfunction, and senescence are commonly observed in the setting of cancer progression, with a pronounced restriction amongst CD8+ T effector cells, which are known for their capacity to mediate tumor regression [1]. Adult thymopoiesis has been reported to increase after growth hormone therapy [4] and pharmacologic androgenic blockade [5]. In HIVinfected patients, thymus-derived CD4+ T cells are known to increase in frequency after antiretroviral therapy [6]. In tumor-bearing hosts, the thymus may contribute principally to the development of regulatory T cells at the expense of effector T cells [7] and/or to the interruption of CD4+CD8+ DP immature thymocyte programming [8, 9]
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