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Review
. 2013 Jul 25;39(1):61-73.
doi: 10.1016/j.immuni.2013.07.005.

Deciphering and reversing tumor immune suppression

Greg T Motz  1 , George Coukos
Affiliations
Review

Deciphering and reversing tumor immune suppression

Greg T Motz (VSports最新版本) et al. Immunity. .

Abstract

Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack VSports手机版. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients. .

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Figures (V体育安卓版)

Figure 1
Figure 1
Generation of an anti-tumor T cell response. Dendritic cells acquire tumor antigens from necrotic or apoptotic tumor cells, and then home to regional lymph nodes. Within the lymph nodes, DCs activate T cells (and NK cells) and they then traffic to the tumor site. Activated lymphocytes cross the tumor endothelial barrier, recognize tumor targets, and secrete cytokines and directly kill tumor targets. This process is under considerable suppression from the tumors, as they mount challenges to each step that prevents optimal T cell activation. Within the tumor site, suppressive cells like Tregs and MDSC are recruited by tumors and actively suppress lymphocytes from killing tumor targets.
Figure 2
Figure 2
Tumor endothelium in immune suppression. A, The endothelium is a physical barrier to T cell trafficking. During the normal inflammatory response, TNFα upregulates adhesion molecules ICAM and VCAM. While rolling, T cells bind to the adhesion molecules through LFA-1 and VLA-1, followed by extravasation through the endothelium and home to the site of inflammation. In the tumor microenvironment, tumor-derived angiogenic growth factors such as VEGF and ET-1 signal through their cognate receptors on the endothelium and block the expression of adhesion molecules, preventing T cell infiltration. B, The endothelium is a direct modulator of immune suppression. Under the influence of tumor- and stromal-derived factors (e.g., VEGF), the tumor endothelium expresses a number of immunosuppressive molecules such as TIM-3, IDO, PDL1/2, and PGE2. The expression of these molecules limit effector T cell activation. Further, the endothelium can also express a number of genes (e.g., TRAIL) that can directly kill effector T cells as they attempt to transverse the endothelial barrier.
Figure 2
Figure 2
Tumor endothelium in immune suppression. A, The endothelium is a physical barrier to T cell trafficking. During the normal inflammatory response, TNFα upregulates adhesion molecules ICAM and VCAM. While rolling, T cells bind to the adhesion molecules through LFA-1 and VLA-1, followed by extravasation through the endothelium and home to the site of inflammation. In the tumor microenvironment, tumor-derived angiogenic growth factors such as VEGF and ET-1 signal through their cognate receptors on the endothelium and block the expression of adhesion molecules, preventing T cell infiltration. B, The endothelium is a direct modulator of immune suppression. Under the influence of tumor- and stromal-derived factors (e.g., VEGF), the tumor endothelium expresses a number of immunosuppressive molecules such as TIM-3, IDO, PDL1/2, and PGE2. The expression of these molecules limit effector T cell activation. Further, the endothelium can also express a number of genes (e.g., TRAIL) that can directly kill effector T cells as they attempt to transverse the endothelial barrier.
Figure 3
Figure 3
After arrival within the tumor microenvironment, effector T cell functions are suppressed by a number of mechanisms including interactions with both soluble and cell surface-expressed mediators.
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