RESUMEN
Background: Colorectal cancer (CRC) is a heterogeneous disease that complicates predicting patients' prognosis and their response to treatment. CRC prognosis is influenced by the tumor microenvironment (TME). The immune system is a critical component of the TME. Programmed cell death receptor 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (Tim3) are inhibitory immune checkpoints that regulate immune response and may provide prognostic power. However, the effect of their expressions and co-expressions on the CRC prognosis remains unclear. Accordingly, this study aimed to investigate the prognostic value of the CD8, CD3, PD-1, Tim3 expression, and PD-1/Tim3 co-expression in patients with CRC. Materials and Methods: One hundred and thirty six patients with CRC who underwent curative surgery were enrolled in the study. Immunohistochemical staining was performed for PD-1, Tim3, CD8, and CD3, and the expression of each marker was evaluated in the center of the tumor (CT), invasive margin (IM), and adjacent normal-like tissue. Result: Our results indicated that high expression of PD-1 in IM was significantly associated with lower TNM stage, T-stage, M-stage, lack of metastasis, the presence of tertiary lymphoid structure (TLS), lack of recurrence (in the left-sided tumors), and larger tumor size (in right-sided tumors) (P<0.05). High expression of PD-1 in IM was also associated with improved overall survival (OS) in a subgroup of patients with high CD8 expression. High Tim3 expression in CT was associated with higher M-stage (M1) (in left-sided CRCs) (P<0.05). It was also associated with decreased OS in total cohort and left-sided CRCs and represented an independent prognostic factor for CRC patients in multivariate analysis. PD-1 and Tim3 co-expression had no synergistic effects on predicting OS. Conclusion: Our findings suggest that the clinicopathological and prognostic significance of immune system-related markers such as CD8, PD-1, and Tim3 depends on the primary tumor sides. We also showed that Tim3 could act as a prognostic factor and therapeutic target in CRC. This marker is probably a more preferred target for immunotherapy than PD-1, especially in left-sided CRCs.
RESUMEN
BACKGROUND: It is well-documented that the interplay between tumor-infiltrating lymphocytes (TILs) and tumor cells is a major determining factor in cancer progression. CD45RO seems to be a reliable indicator for predicting prognosis and disease outcome, along with CD3 and CD8 markers. LAG-3 is another important marker that overexpresses on TILs in a variety of cancers and is associated with disease prognosis; however, its prognostic impact is controversial. Hence, in the present study, we aimed to investigate the presence of CD45RO + , LAG3 + , CD3 + , and CD8 + lymphocytes in CRC tumor tissues and their association with clinicopathological parameters of the disease as well as patients' survival, according to primary tumor locations. METHODS: Expression of CD45RO, LAG3, CD3, and CD8 was immunohistochemically assessed in tissue sections of 136 patients with CRC. The percentages of TILs expressing these markers were then separately determined in both invasive margin (IM) and center of tumor (CT). Their associations with clinicopathological factors and patients' survival were analyzed in the entire cohort and the subgroups of patients with right- and left- rectum tumors. RESULTS: Based on our observation, CD45RO + and CD3 + cells were the most frequent infiltrated lymphocytes in both CT and IM regions of colon tumor tissue. Whilst, LAG3 + lymphocytes were the least frequent subset in both areas. Statistical analysis indicated that the frequency of CD45RO + TILs was positively associated with advanced TNM stages (III/IV), in the entire cohort and right-sided tumors (P < 0.05). LAG3 + TILs in IM were also increased in tumor tissues with higher T-stages in the entire cohort (P = 0.027). In univariate analysis, high score of CD45RO + TILs in IM was associated with better overall survival in the entire cohort. High score of CD8 + and CD45RO + lymphocytes in IM were also associated with improved survival in patients with right-sided tumors. CONCLUSIONS: Our findings generally suggest that the clinicopathological and prognostic significance of immune system-related markers such as CD45RO and LAG3 depends on the primary tumor sides. Our results collectively demonstrated that infiltration of CD45RO + lymphocytes in IM could be an independent prognostic factor in a site-dependent manner.