Co-expression of PD-1 with TIGIT or PD-1 with TIM-3 on tumor-infiltrating CD8(+) T cells showed synergistic effects on improved disease-free survival in treatment-naïve CRC patients.

Immune checkpoints (ICs) are highly expressed on tumor-infiltrating immune cells (TIICs) in different malignancies, including colorectal cancer (CRC). T cells play crucial roles in shaping CRC, and their presence in the tumor microenvironment (TME) has proven to be one of the best predictors of clinical outcomes. A crucial component of the immune system is cytotoxic CD8+ T cells (CTLs), which play decisive roles in the prognosis of CRC. In this study, we investigated associations of immune checkpoints expressed on tumor-infiltrating CD8+ T cells with disease-free survival (DFS) in 45 naïve-treatment CRC patients. First, we examined the associations of single ICs, and found that CRC patients with higher levels of T-cell immunoglobulin and ITIM-domain (TIGIT), T-cell immunoglobulin and mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) CD8+ T cells tended to have longer DFS. Interestingly, when PD-1 expression was combined with other ICs, there were more evident and stronger associations between higher levels of PD-1+ with TIGIT+ or PD-1+ with TIM-3+ tumor-infiltrating CD8+ T cells and longer DFS. Our findings for TIGIT were validated in The Cancer Genome Atlas (TCGA) CRC dataset. This study is the first to report on the association of co-expression of PD-1 with TIGIT and PD-1 with TIM-3 in CD8+ T cells and improved DFS in treatment-naïve CRC patients. This work highlights the significance of immune checkpoint expression on tumor-infiltrating CD8+ T cells as critical predictive biomarkers, especially when co-expression of different ICs is considered.

Meyiah A ，Mahmoodi Chalbatani G ，Al-Mterin MA ，Malekraeisi MA ，Murshed K ，Elkord E ... -  《-》

PD-1 expression, among other immune checkpoints, on tumor-infiltrating NK and NKT cells is associated with longer disease-free survival in treatment-naïve CRC patients.

A variety of variables, such as microsatellite instability or inflammatory mediators, are critical players in the development and progression of colorectal cancer (CRC). Natural killer (NK) and natural killer T (NKT) cells are involved in the prognoses of CRC. Immunological components of the tumor microenvironment (TME) impact cancer progression and therapeutic responses. We report that CRC patients with higher frequencies of tumor-infiltrating PD-1+ NK and NKT cells had significantly longer disease-free survival (DFS) than patients with lower frequencies. In agreement with that, patients with higher frequencies of tumor-infiltrating PD-1- NK and NKT cells showed shorter DFS. There were no significant associations between tumor-infiltrating PD-1+TIM-3+, PD-1+TIGIT+, PD-1+ICOS+, PD-1+LAG-3+ NK cells, and PD-1+TIM-3+, PD-1+TIGIT+, and PD-1+LAG-3+ NKT cells with DFS. This study highlights the significance of PD-1 expression on tumor-infiltrating NK and NKT cells and its association with disease prognoses in CRC patients.

Al-Mterin MA ，Murshed K ，Elkord E 《-》

High co-expression of immune checkpoint receptors PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT on tumor-infiltrating lymphocytes in early-stage breast cancer.

High expression of immune checkpoint receptors (ICRs) in the tumor microenvironment regulates the anti-tumor response. In this study, the differential expressions of ICRs on tumor-infiltrating lymphocytes (TILs) in patients with early-stage breast cancer were investigated.The study included 32 patients who underwent surgery with a diagnosis of early-stage breast cancer between September 2018 and March 2020. TIL isolation was performed using a MACS tumor separation device and tumor separation kit. PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT expression of cytotoxic T and natural killer (NK) cells on TILs and peripheral blood lymphocytes (PBLs) were determined by flow cytometry.Patients with a high Ki-67 index, high TIL density, and HER-2 positivity were more likely to have increased CD16+CD56dim NK cells on TILs. Patients with T2 tumors were more likely to have increased expression of PD-1, LAG-3, and TIGIT on tumor-infiltrating CD8+ cytotoxic T cells than those with T1 tumors. PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 expression of CD8+ T and CD16-CD56bright NK cells in TILs showed significant positive correlations with each other. PD1+CD8+, TIGIT+CD16+, and CTLA-4+CD56+ cells in PBLs and TILs were found to be negatively correlated, whereas only TIM-3+ expression of CD8+ T and CD16+CD56dim cells in PBLs and TILs showed positive correlations.Our results suggest that CD16+CD56dim NK cells on TILs may play a major role in the immune response against HER2-positive or highly proliferating breast tumors in patients with early-stage breast cancer. Furthermore, various ICRs were found to be highly co-expressed with each other on TILs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT. These receptors may synergistically suppress the response to the tumor, which may trigger immune escape mechanisms in the early stage of carcinogenesis. However, ICR expressions other than TIM3 on PBLs were not found to accompany their counterparts on TILs.

Mollavelioglu B ，Cetin Aktas E ，Cabioglu N ，Abbasov A ，Onder S ，Emiroglu S ，Tükenmez M ，Muslumanoglu M ，Igci A ，Deniz G ，Ozmen V ... -  《World Journal of Surgical Oncology》

DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer.

Sasidharan Nair V ，Toor SM ，Taha RZ ，Shaath H ，Elkord E ... -  《-》

Expression of immune checkpoints in T cells of esophageal cancer patients.

Xie J ，Wang J ，Cheng Sh ，Zheng L ，Ji F ，Yang L ，Zhang Y ，Ji H ... -  《Oncotarget》