Ectopic Expression of TIM-3 in Lung Cancers
TIM-3 was originally identified through a screen for Th1-specific markers. Since then, it has also been found on cytotoxic CD8+ T cells, Th17, Treg, monocytes, dendritic cells, mast cells, circulating natural killer (NK) cells, and melanoma cells. Here, to our knowledge for the first time, we demonstrated TIM-3 expression in tumor cells from patients with NSCLC whereas normal lung tissues lacked any positive expression of TIM-3. In addition, we found a statistically significant correlation between TIM-3 protein expression in tumor cells and the clinicopathologic parameters of nodal status and disease stage. More importantly, we found that the 5-year survival rate of patients with moderate/strong TIM-3 expression tumors was significantly lower than those with weak/negative TIM-3 expression. The univariate and multivariate analyses revealed that TIM-3 status in tumor cells may become an independent predictor for the prognosis of NSCLC. This suggests that TIM-3 status could be a valuable marker for monitoring chemotherapy as well. Further investigations with a larger scale of NSCLC samples and longer follow-up periods are needed to establish the role of TIM-3 in predicting the prognosis and therapeutic effect in these patients.
TIM-3 protein was expressed in 86.7% of detected NSCLC specimens, in which a majority (57.7%) exhibited a moderate/strong TIM-3 expression. Moreover, we found that most tumor cells were TIM-3–positive staining. However, the mechanisms for regulating TIM-3 expression in tumor cells are not yet fully understood. Wiener et al reported that TGF-β1 elevated TIM-3 expression, which resulted in local immunosuppression. TGF-β1 plays an important role in the development of NSCLC and can be produced by both lung tumor cells and infiltrated lymphocytes. Thus, the aberrant expression of TIM-3 in lung cancer cells may be because of the cytokine produced during the process of NSCLC malignant transformation.
Published data suggest that the expression of TIM-3 interferes with the function of immunocompetent T and NK cells, but the roles of TIM-3 expression in tumor cells are largely unknown. Huang et al found that endothelial cell–expressed TIM-3 facilitates the onset, growth, and dissemination of lymphoma by suppressing activation of CD4+ T cells and Th1 polarization through the activation of the interleukin-6–STAT3 pathway. The TIM-3 expressed in lung tumor cells may work in a similar way, and its expression in malignant cells may represent one of the various mechanisms used by the tumor cells to escape immune surveillance. Tumor-infiltrated immunocytes play a role in inflammation-associated carcinogenesis. Yasumoto et al indicated that TILs play a key role in the host defense against tumor, mainly through TAMs in patients with primary lung cancer. Although TILs did not exhibit any cytolytic activity against various target cells the average percentage of TILs was higher in patients without recurrence than in those with recurrence 2 years after complete resection of lung cancer. The average cytostatic activity of TAMs was high in patients without recurrence, and the activity of macrophage-activating factor induced by TIL was also higher in patients showing no recurrence suggesting that antitumor activity of TAMs may be controlled by specifically sensitized TIL through lymphokines. In our previous report, we also demonstrated the positive correlation between increased TILs, especially CD8+ T cells and longer survival in NSCLC. In this report, we found no definite correlation between TIM-3 expression and host immune response, possibly because of the small sample size. However, our data indicate that TIM-3 increased by immune response (frequency of moderate/strong host immune response is higher in patients with TIM-3–negative tumors than in those with TIM-3–positive tumors; Table 2), which may be because of T cell activation. However, the increased TIM-3 expression is accompanied by weak host immune response (frequency of moderate/strong host immune response is higher in patients with weak TIM-3 expression tumors than in those with moderate/strong TIM-3 expression tumors; Table 2). This is consistent with the previous report that TIM-3 expression plays an important negative role in Th1 and Tc1 immunity. Our finding of a negative correlation between TIM-3 expression in tumor cells and host immune responses suggests that the induction of TIM-3 in tumor cells may be one of the mechanisms for immune repression in patients with NSCLC. Further study on the correlation among TIM-3, TILs, and TAMs, in a larger sample, may provide additional evidence to support the hypothesis.
In conclusion, for the first time we have demonstrated the expression of TIM-3 in tumor cells from patients with NSCLC. Most importantly, the univariate and multivariate analyses revealed the significant role of TIM-3 as an independent prognostic factor for patients with NSCLC. Thus, the status of TIM-3 could be determined on clinical examination and immunohistochemical analysis.
Discussion
TIM-3 was originally identified through a screen for Th1-specific markers. Since then, it has also been found on cytotoxic CD8+ T cells, Th17, Treg, monocytes, dendritic cells, mast cells, circulating natural killer (NK) cells, and melanoma cells. Here, to our knowledge for the first time, we demonstrated TIM-3 expression in tumor cells from patients with NSCLC whereas normal lung tissues lacked any positive expression of TIM-3. In addition, we found a statistically significant correlation between TIM-3 protein expression in tumor cells and the clinicopathologic parameters of nodal status and disease stage. More importantly, we found that the 5-year survival rate of patients with moderate/strong TIM-3 expression tumors was significantly lower than those with weak/negative TIM-3 expression. The univariate and multivariate analyses revealed that TIM-3 status in tumor cells may become an independent predictor for the prognosis of NSCLC. This suggests that TIM-3 status could be a valuable marker for monitoring chemotherapy as well. Further investigations with a larger scale of NSCLC samples and longer follow-up periods are needed to establish the role of TIM-3 in predicting the prognosis and therapeutic effect in these patients.
TIM-3 protein was expressed in 86.7% of detected NSCLC specimens, in which a majority (57.7%) exhibited a moderate/strong TIM-3 expression. Moreover, we found that most tumor cells were TIM-3–positive staining. However, the mechanisms for regulating TIM-3 expression in tumor cells are not yet fully understood. Wiener et al reported that TGF-β1 elevated TIM-3 expression, which resulted in local immunosuppression. TGF-β1 plays an important role in the development of NSCLC and can be produced by both lung tumor cells and infiltrated lymphocytes. Thus, the aberrant expression of TIM-3 in lung cancer cells may be because of the cytokine produced during the process of NSCLC malignant transformation.
Published data suggest that the expression of TIM-3 interferes with the function of immunocompetent T and NK cells, but the roles of TIM-3 expression in tumor cells are largely unknown. Huang et al found that endothelial cell–expressed TIM-3 facilitates the onset, growth, and dissemination of lymphoma by suppressing activation of CD4+ T cells and Th1 polarization through the activation of the interleukin-6–STAT3 pathway. The TIM-3 expressed in lung tumor cells may work in a similar way, and its expression in malignant cells may represent one of the various mechanisms used by the tumor cells to escape immune surveillance. Tumor-infiltrated immunocytes play a role in inflammation-associated carcinogenesis. Yasumoto et al indicated that TILs play a key role in the host defense against tumor, mainly through TAMs in patients with primary lung cancer. Although TILs did not exhibit any cytolytic activity against various target cells the average percentage of TILs was higher in patients without recurrence than in those with recurrence 2 years after complete resection of lung cancer. The average cytostatic activity of TAMs was high in patients without recurrence, and the activity of macrophage-activating factor induced by TIL was also higher in patients showing no recurrence suggesting that antitumor activity of TAMs may be controlled by specifically sensitized TIL through lymphokines. In our previous report, we also demonstrated the positive correlation between increased TILs, especially CD8+ T cells and longer survival in NSCLC. In this report, we found no definite correlation between TIM-3 expression and host immune response, possibly because of the small sample size. However, our data indicate that TIM-3 increased by immune response (frequency of moderate/strong host immune response is higher in patients with TIM-3–negative tumors than in those with TIM-3–positive tumors; Table 2), which may be because of T cell activation. However, the increased TIM-3 expression is accompanied by weak host immune response (frequency of moderate/strong host immune response is higher in patients with weak TIM-3 expression tumors than in those with moderate/strong TIM-3 expression tumors; Table 2). This is consistent with the previous report that TIM-3 expression plays an important negative role in Th1 and Tc1 immunity. Our finding of a negative correlation between TIM-3 expression in tumor cells and host immune responses suggests that the induction of TIM-3 in tumor cells may be one of the mechanisms for immune repression in patients with NSCLC. Further study on the correlation among TIM-3, TILs, and TAMs, in a larger sample, may provide additional evidence to support the hypothesis.
In conclusion, for the first time we have demonstrated the expression of TIM-3 in tumor cells from patients with NSCLC. Most importantly, the univariate and multivariate analyses revealed the significant role of TIM-3 as an independent prognostic factor for patients with NSCLC. Thus, the status of TIM-3 could be determined on clinical examination and immunohistochemical analysis.