Can the assessment of lymphocyte exhaustion serve as a prognostic predictor after lung cancer surgery?

Transl Lung Cancer Res 2020 | http://dx.doi. org/10.21037/tlcr.2020. 03.21 T-cell receptors (TCRs) and costimulatory receptors—both activating signals—are directed for differentiation of T-cells in the direction of through to effector cells. Notably, both TCRs and costimulatory receptors can be suppressed by different signals. Costimulatory receptors coordinate the induction of antigen-specific signals from TCRs, including a group of inhibitory immune-checkpoint molecules that comprise cytotoxic T-cell antigen-4 (CTLA-4), programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucindomain containing-3 (TIM-3) (1). TIM-3 belongs to a family of type I membrane proteins and suppresses IFN-γ production in Th1 cells (2). It is commonly expressed in exhausted T-cells with other checkpoint receptors (3). However, the mechanisms by which TCRs and other factors regulate TIM-3 expression are not well characterized. Equivalently, a majority of tumor-infiltrating lymphocytes (TILs) in tumors express TIM-3, but it is unclear what roles in the microenvironment of tumor or which tumor antigens are involved in the elevation of TIM-3 in effector T-cells and Treg cells. TIM-3 elevation, as well as the elevation of other checkpoint receptors, is correlated with CD8+Tcell exhaustion. About melanoma, elevation of both PD-1 and TIM-3 is a good indicator of non-reactive CD8+Tcell populations (4). It has also been shown that TIM3 is expressed on tumor antigen-specific T-cells in the peripheral blood of patients with various tumors, and several recent reports have demonstrated that TIM-3 is also expressed on tumor cells themselves (5-7). It was suggested that the expression of TIM-3 on tumor cells might directly promote tumor metastasis and result in tumor advance by other mechanisms. These mechanisms include direct suppression of CD4+T-cell function and suppression of IL-6 to STAT3 signaling. Against this background, TIM-3 has been suggested to be a predictive marker for poor survival outcomes in a wide variety of malignancies, including prostatic and renal cell carcinomas, as well as in colorectal and gastric cancers (8). In this study, they evaluated the expression of TIM3 in surgically resected lung cancer specimens. This study included 139 patients who had not received any preoperative treatment. More than 10% of the TILs and more than 5% of the tumor cells were positive for TIM3. Results showed that 7.9% (11 cases) of TILs and 6.5% (9 cases) of tumor cells were TIM3 positive, and that there was no correlational statistics between TIM-3 expression and clinical characteristics. Notably, they evaluated the coexpression patterns of TIM-3 with PD-1 and PD-L1 in TILs. Previously, the co-expression of PD-1(+) TIM-3(+) was considered to be indicative of exhausted T-cells (9), which correlated with poor prognostic factors in ovarian cancers (10). Although they did not analyze prognostic factors for coexpression, high TIM-3 levels in TILs were associated with significantly shorter recurrence-free survival (RFS), overall survival (OS), and poorer prognosis. The lack of correlation Editorial