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.

Associations of different immune checkpoints-expressing CD4+ Treg/ T cell subsets with disease-free survival in colorectal cancer patients.

There are different subsets of T regulatory cells (Tregs), orchestrating critical roles in the regulation of anti-tumor immunity in colorectal cancer (CRC). In this study, we report that a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer disease-free survival (DFS), while their higher frequencies in tumor-infiltrating CD4+ Tregs was associated with better DFS. We further investigated such associations with four Tregs/T cells expressing or lacking FoxP3 and Helios (FoxP3±Helios±). For the first time, we report that a high frequency of circulating CD4+FoxP3+Helios+ Tregs was associated with poorer DFS, while a high frequency of tumor-infiltrating CD4+FoxP3-Helios- T cells was associated with poorer DFS. In the four FoxP3±Helios± T cell subsets expressing any of the immune checkpoints (ICs) investigated, we found that a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. We also found that high frequencies of FoxP3+Helios+CTLA-4+ Tregs, FoxP3+Helios-CTLA-4+ Tregs, and FoxP3-Helios+CTLA-4+ CD4+ T cells in circulation were associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Our data show that certain CD4+ Treg/T cell subsets could serve as independent predictive biomarkers in CRC patients. Identification of the exact subpopulations contributing to clinical outcomes is critical for prognoses and therapeutic targeting.

Inhibitory Immune Checkpoint Receptors and Ligands as Prognostic Biomarkers in COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. During T-cell activation, the immune system uses different checkpoint pathways to maintain co-inhibitory and co-stimulatory signals. In COVID-19, expression of immune checkpoints (ICs) is one of the most important manifestations, in addition to lymphopenia and inflammatory cytokines, contributing to worse clinical outcomes. There is a controversy whether upregulation of ICs in COVID-19 patients might lead to T-cell exhaustion or activation. This review summarizes the available studies that investigated IC receptors and ligands in COVID-19 patients, as well as their effect on T-cell function. Several IC receptors and ligands, including CTLA-4, BTLA, TIM-3, VISTA, LAG-3, TIGIT, PD-1, CD160, 2B4, NKG2A, Galectin-9, Galectin-3, PD-L1, PD-L2, LSECtin, and CD112, were upregulated in COVID-19 patients. Based on the available studies, there is a possible relationship between disease severity and increased expression of IC receptors and ligands. Overall, the upregulation of some ICs could be used as a prognostic biomarker for disease severity.

Correlations between Circulating and Tumor-Infiltrating CD4+ T Cell Subsets with Immune Checkpoints in Colorectal Cancer.

T regulatory cells (Tregs) play different roles in the regulation of anti-tumor immunity in colorectal cancer (CRC), depending on the presence of different Treg subsets. We investigated correlations between different CD4+ Treg/T cell subsets in CRC patients with immune checkpoint-expressing CD4+ T cells. Positive correlations were observed between levels of different immune checkpoint-expressing CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 with FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios- Tregs in the tumor microenvironment (TME). However, negative correlations were observed between levels of these immune checkpoint-expressing CD4+ T with FoxP3-Helios- T cells in the TME. These correlations in the TME highlight the role of cancer cells in the upregulation of IC-expressing Tregs. Additionally, positive correlations were observed between levels of FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios- Tregs and levels of CD4+CTLA-4+ T cells and CD4+PD-1+ T cells in peripheral blood mononuclear cells (PBMCs) and normal tissue-infiltrating lymphocytes (NILs). These observations suggest that CTLA-4 and PD-1 expressions on CD4+ T cell subsets are not induced only by the TME. This is the first study to investigate the correlations of different FoxP3+/-Helios+/- T cell subsets with immune checkpoint-expressing CD4+ T cells in CRC patients. Our data demonstrated strong correlations between FoxP3+/Helios+/- Tregs but not FoxP3-Helios+/- non-Tregs and multiple immune checkpoints, especially in the TME, providing a rationale for targeting these cells with highly immunosuppressive characteristics. Understanding the correlations between different immune checkpoints and Treg/T cell subsets in cancer patients could improve our knowledge of the underlying mechanisms of Treg-mediated immunosuppression in cancer.

Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19.

Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammation-induced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.

Myeloid-derived suppressor cells in colorectal cancer: prognostic biomarkers and therapeutic targets.

Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells, which are expanded in most cancer patients. MDSCs suppress host immune responses, leading to cancer growth and progression. Several studies demonstrated that there was a relationship between levels of MDSCs and tumorigenesis in colorectal cancer (CRC) patients. MDSCs are now being investigated for their role as possible therapeutic targets in cancer treatment. This review summarizes available studies that investigated MDSC expansion in CRC patients, as well as their role in CRC tumorigenesis, prognosis, and targeting. Based on the available studies, there is a possible relationship between high levels of MDSCs and CRC progression. Additionally, targeting MDSCs in CRC patients selectively represents a significant challenge for the development of targeted treatments. Targeting of MDSCs could be exploited in different ways including MDSC depletion, inhibition of MDSC function and recruitment, and enhancing MDSC differentiation. Overall, MDSCs could be exploited as prognostic biomarkers and potential therapeutic targets in CRC.

Correlations between Circulating and Tumor-Infiltrating CD4+ Treg Subsets with Immune Checkpoints in Colorectal Cancer Patients with Early and Advanced Stages.

The existence of various T regulatory cell (Treg) subsets in colorectal cancer (CRC) could play a variety of functions in the regulation of anti-cancer immunity. We studied correlations between CD4+ Treg subsets with the expression of immunological checkpoints on CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 in CRC patients with early and advanced TNM staging. Strong positive correlations were found between frequencies of FoxP3+ Tregs and FoxP3+Helios+ Tregs with frequencies of various immune checkpoint-expressing CD4+ T cells in the tumor microenvironment (TME). However, there were strong negative correlations between frequencies of FoxP3-Helios- T cells and these immune checkpoint-expressing CD4+ T cells. Specifically, in the TME, we found that the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, FoxP3+Helios- Tregs, and FoxP3-Helios- T cells with CD4+LAG-3+ T cells and CD4+CTLA-4+ T cells were higher in patients with early stages, suggesting the potential of these highly immunosuppressive cells in inhibiting inflammatory responses in the TME. However, the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, and FoxP3-Helios- T cells with CD4+TIM-3+ T cells were higher in patients with advanced stages. This is the first study to explore correlations of Treg subpopulations with immune checkpoint-expressing CD4+ T cells in CRC based on clinicopathological features of CRC patients. The findings of our study provide a justification for focusing on these cells that possess highly immunosuppressive features. Understanding the correlations between different immune checkpoints and Treg subsets in CRC patients has the potential to enhance our understanding of core mechanisms of Treg-mediated immunosuppression in cancer.

Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.

Circulating and Tumor-Infiltrating Immune Checkpoint-Expressing CD8+ Treg/T Cell Subsets and Their Associations with Disease-Free Survival in Colorectal Cancer Patients.

T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios-TIM-3+ Tregs were associated with better DFS.