Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8⁺ T cell tolerance

Abstract

Development of tumor-specific T cell tolerance contributes to the failure of the immune system to eliminate tumor cells. Here we report that hematogenous dissemination of tumor cells followed by their elimination and local removal of apoptotic tumor cells in the liver leads to subsequent development of T cell tolerance towards antigens associated with apoptotic tumor cells. We provide evidence that liver sinusoidal endothelial cells (LSEC) remove apoptotic cell fragments generated by induction of tumor cell apoptosis through hepatic NK1.1 + cells. Antigen associated with apoptotic cell material is processed and cross-presented by LSEC to CD8 + T cells, leading to induction of CD8 + T cell tolerance. Adoptive transfer of LSEC isolated from mice challenged previously with tumor cells promotes development of CD8 + T cell tolerance towards tumor-associated antigen in vivo. Our results indicate that hematogenous dissemination of tumor cells, followed by hepatic tumor cell elimination and local crosspresentation of apoptotic tumor cells by LSEC and subsequent CD8 + T cell tolerance induction, represents a novel mechanism operative in tumor immune escape. IntroductionThe liver is often a site of tumor metastasis once tumor cells reach the circulation. In particular for tumors arising in the gastrointestinal tract, the liver represents the first vascular bed that allows tumor seeding or promotes tumor elimination. The molecular mechanisms involved in tumor cell adhesion within the liver have been partly elucidated and are critical in the initiation of metastasis [1]. There is mutual interaction between liver sinusoidal cells and tumor cells, which involves the mannose receptor, release of IL-1b and IL-18 as well as endothelial cell up-regulation of adhesion molecules such as VCAM-1 [2], which all favor the development of hepatic metastasis.At the same time, hepatic sinusoidal cell populations contribute to tumor defense. Kupffer cells as the hepatic macrophage population have the capacity to kill tumor cells efficiently through phagocytosis [3] and induction Immunomodulation * These authors contributed equally to this work. ** These authors are co-senior authors.Correspondence: Percy A. Knolle [7]. These cells efficiently eliminate metastasizing tumor cells through induction of apoptosis through TRAIL, CD95L or the perforin/granzyme B pathway [8][9][10][11]. The hepatic overall capacity to eliminate tumor cells seems to be linked to the physiological role of the liver to eliminate gut-derived material from portal venous blood, because the hepatic activity of tumor cell killing is reduced in germ-free mice [12]. Furthermore, the liver is known to remove activated T cells from the circulation. Bone marrowderived as well as organ-resident hepatic cell populations attract circulating activated T cells employing CD54/CD106 and induce T cell apoptosis [13][14][15]. This similarity in retention and elimination of tumor cells and activated T cells suggests that not only may similar molecular mechanisms be employed, but also t...

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

“…25 LSEC, a unique liver-resident APC population, can also induce CD8 ϩ T cell tolerance toward cross-presented exogenous antigens. [21][22][23][24] We now show that CD8 ϩ T cell tolerance induction by LSEC is a B7-H1-dependent nondeletional process that involves mutual stimulation of both LSEC and CD8 ϩ T cells as a licensing step preceding the induction of T cell tolerance.…”

“…21,22 LSEC initially stimulate naïve T cells but fail to support differentiation into effector cells, and induce T cell tolerance 21,22 toward antigens derived from the gastrointestinal tract 23 and from apoptotic cells. 24 Here, we report that LSEC undergo tolerogenic maturation, independent of exogenously added mediators, that necessitates cognate interaction with naive CD8 ϩ T cells. This interaction promotes licensing of LSEC for delivery of B7-H1-dependent co-inhibitory signals and of LSEC-stimulated CD8 ϩ T cells for receiving tolerogenic signals via programmed death 1 (PD-1).…”

“…We have previously shown that LSEC induce CD8 ϩ T cell tolerance in vitro and in vivo. 21,23,24 Here we investigated the molecular mechanisms underlying stimulation and tolerance induction in naïve CD8 T cells by antigen-presenting LSEC. Antigen-presenting LSEC initially stimulated T cells to increase expression of CD25, CD44, and PD-1 and to down-regulate CD62L within 24 hours (Fig.…”

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation

“…Detection intracellular interferon gamma (IFN-␥) production was performed as described. 17 In Vivo Cytotoxicity Assay. For cell adoptive transfers, 1e6 CD8 ϩ purified naive OT I T cells were injected in 200 L phosphate-buffered saline via the tail vein.…”

Potential of tumour cells for delivering oncolytic viruses

“…In particular, presentation by liver sinusoidal endothelial cells of antigens derived from apoptotic tumour cells appears to be tolerogenic for CD8+ T cells. 18 Infection of ATCs might shift the immune balance in favour of vaccination. For example, the fusion of tumour cells due to expression of viral fusogenic membrane glycoproteins can reverse their suppressive effects on dendritic cells.…”