Volume 6 Issue 5 - November 07, 2008
To die or not to die, that depends on the tissue environment: Tumor extracellular matrix shapes the Fas-meditated apoptosis in T cells.
Bei-Chang Yang


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Apoptosis triggered by Fas (CD95, Apo1) receptor is one of the important ways to regulate the biological functions at cellular level. Delayed Fas-mediated apoptosis in immune cells associates with many pathological inflammatory consequences. During tumor formation, inadequate accumulation of infiltrating immune cells, mainly due to defective Fas death signaling, may play an adverse role. Pieces evidence support that tumors may high-jack accumulated infiltrating immune cells to create a tumor growth-promoting environment; this event occurs by the evasion of immune surveillance using elevated local production of IL-10, an immune-suppressive cytokines, and increased VEGF, a growth factor stimulating angiogenesis to bring in nutrition. Autoimmunity represents another pathological feature of delayed apoptosis in activated immune cells, which develops into uncontrolled inflammation. Thus, understanding the aberrant apoptosis in immune cells is an issue with therapeutic application. The mechanism conferring better viability of immune cells in the tumor tissue environment is still poorly understood. Recent knowledges about tissue environment underscore the importance of the extracellular matrix (ECM) in decisions involving the life and death of cells. By inflammation and tumorigenesis, the local status of the ECM may be profoundly perturbed. Tumors secrete various ECM components and metalloproteases in abundance, thereby altering the makeup of the immediate tissue environment.

Fig. 1. Engagement of T cells with tumor matrix initiates PI3K/Akt pathway which suppresses the formation of DISC, stabilizes Bck-xL and phosphorulates Bad protein at Ser 136 site. As a result, T cells in tumor tissue are insensitive to Fas-mediated apoptosis.
We undertook this question by setting up an in vitro co-culture system allowing immune cells to get into contact with a tumor cell layer mimicking the scenario in a tumor region (Su et al 2007). We evaluated the Fas-mediated apoptosis in T cells, being major effective immune cells for tumor surveillance, in this context of tumor cells contact. We found that cell-to-cell contact with tumor cells reduced Fas signal-mediated apoptosis in Jurkat T cells and activated primary human peripheral T cells. This protection ability was tumor cell line-specific. Even cells of same tumor type, such as hepatoma cell lines Huh-7 and HepG2, showed different protection abilities; the former was protective, but the latter was not. In parallel with a better viability, the apoptotic program in those tumor-protected T cells was impaired including receptor/DISC formation, mitochondrial membrane disruption, and death-executive proteases activation. Furthermore, the PI3K/Akt pathway in T cells is activated through cell-cell interaction, engagement of integrin β1/2 of T cells with ECM ligands of tumors, and this is essential to the prevention of apoptosis in T cells. Our findings provide a mechanistic rational to explain the accumulation of T cells within tumor tissues and highlight the role of the tumor matrix in providing PI3K/Akt survival signals for T cells and this is illustrated in the summary Figure 1 showed. Previously, we have demonstrated that tumors are able to highjack immune cells in order to create an immune suppressive environment by producing IL-10 (Yang BC, et al. 2003). The study about tumor matrix suggest that cell contact and PI3K/Akt play a key role in delaying the apoptotic program in T cells and this provides a frame work for further analysis of the tumor matrix and immune regulation. Autoimmunity is another area that is of pathological relevance to the above findings. Local integrin-matrix interactions in inflamed tissues may provide a survival signal that leads to the expansion of the potentially autoreactive T cells that are present in the immune repertoire. If this holds true, then the integrin-matrix/PI3K/Akt pathway may be a potential target for the treatment of inflammatory disease.

References:

1Su CC, Lin YP, Cheng YJ, Huang JY, Chuang WJ, Shan YS, Yang BC (2007) Phosphatidylinositol 3-kinase/akt activation by integrin-tumor matrix interaction suppresses fas-mediated apoptosis in T cells. J Immunol. 179:4589-4597.
2Yang BC, Hor WS, Lin HK, Hwang JY, Lin YP, Liu MY, and Wang YJ (2003) Mediation of enhanced transcription of the IL-10 gene in T cells, upon contact with human glioma cells, by Fas signaling through a protein kinase A-independent pathway. J Immunol. 171:3947-3954.
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