An investigation into the mechanism about the inability of CD8+ T cells in the tumor microenvironment to inhibit tumor growth

• Main Authors: Chiao Wen Kang, 康喬雯
• Other Authors: C.Y.Lin
• Format: Others
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/66870988635385082771

碩士 === 長庚大學 === 生物醫學研究所 === 98 === Tumor microenvironment is regarded as tolerogenic and plays an important role in protecting the tumors from immune attacks. In the previous studies from the host laboratory, it had been shown that CD8+ T cells harvested from spleens of day-28 CT26 tumor-bearing mice could inhibit tumor growth if these cells were adoptively transferred into mice at the time of tumor inoculation. Interestingly, when these CD8+ T cells were adoptively transferred into day-7 tumor-bearing mice, there was no effect on the tumor growth. We reasoned these CD8+ T cells were dysfunctional when migrated into tumor microenvironment of established tumor. We therefore analyzed the phenotype of CD8+ T cells in tumor microenvironment. These tumor-infiltrating lymphocytes (TILs) were with CD44highCD62Llow phenotype and were functionally competent, reflected as enhanced expression of granzyme B and perforin and the ability to synthesize TNF- and IFN- when compared with CD8+ T cells from the spleens of day-28 tumor-bearing mice. In addition, we had shown that these CD8+ T cells possessed the cytolytic activity against CT26 tumor cell lines in vitro and could inhibit tumor growth in vivo by adoptively transferring these cells to one-day tumor bearing mice. However, the CD8+ T cells in TILs were with significantly higher PD-1 and TIM-3 expression and with increased apoptosis. Finally, we also found the expression of galectin-9 in tumor sites. Galectin-9 was known to induce apoptosis of TIM-3 expressing T cells. Therefore, it is possible that galctin-9 could induce the apoptosis of competent CD8+ T cells in the TILs through galectin-9-TIM-3 interaction, which in turn protect the tumor from immune attacks. Taken together, these results suggested that tumor reactive CD8+ T cells in the tumor microenvironment were functionally competent and were not exhausted though with increased expression of PD-1 and TIM-3. However, these CD8+ T cells were highly apoptotic. These results implied that the induction of apoptosis of CD8+ T cells in tumor microenvironment might be an important strategy of tumor cells to evade the immune attacks.