The Biomarkers of Cd4+ T Regulatory Cells Associated with Tumour Immune Escape

Objective: In this review, we endeavor to do a literature search mainly focusing on keywords CD4+FOXP3+, CD4+CD127-, CD4+CD39+, CD4+LAP+ cancer immunotherapy, cancer immunotherapy strategies and articles published between 2015 to 2019 to add onto the minimal defi nition of human Treg, by an international workshop organized by collaborative immunoguiding program. Methodology: In this review, we highlight the antitumor suppressive biomarkers of CD4+ Treg cells, how they suppress the immune response. Summary: The biomarkers play a role in designing of cancer immunotherapy to overcome resistance and enhance anti-tumor immune response among late-stage cancer patients who have exhausted the standard of care. There is evidence suggesting that a combination of treatment strategies has enhanced immune responses for some patients who have developed or are resistant to monoclonal immunotherapy treatments. Review Article The Biomarkers of Cd4+ T Regulatory Cells Associated with Tumour Immune Escape


Introduction
There have been advances made in precision oncology in designing effective immunotherapies against cancer.
However, it does not appear to benefi t all cancer patients, as some have either developed resistance or do not respond at all to FDA approved immunotherapies. And we are yet to understand the mechanism underlying this resistance and why some patients appear to benefi t while others do not. Therefore, it is paramount for us to understand the inhibitory mechanism and synergies between various CD4+ Treg cells associated with tumor immune escape. As such we chose the fi ve subsets as there are several studies done on the post the minimal defi nition of Tregs. The biomarkers expressed of CD4+ Treg cells do make these regulatory cells more potent in suppressing effector immune responses against cancer cells. It is these biomarkers that have been used to monitor the effi cacy of immunotherapy treatments and measure the treatment progress of cancer patients. Therefore, there is a need to design cancer immunotherapies against these antigens to enhance the body's effector immune response against cancer. Some studies suggest that inhibiting the expression of these biomarkers would improve anti-tumor immune response studies such as CD4+FOXP3+ Treg cells suppress the anti-tumor immune response, and it is an indication of poor patient prognosis [1][2][3][4][5][6][7].

Mechanism of tumor immune escape via CD4+CD25+FOXP3+ Treg cells
The fi rst subset of CD4+ Treg cells to be described was the CD4+CD25+FOXP3+ cells discovered in several cancer types where it prevents autoimmune diseases, as activated suppressive markers where it hampered the T eff . The Foxp3 is highly expressed in CD4+ T cells, and inhibit the proliferative activity of naïve CD4+ T cells [7], as it is an intracellular transcription factor and the master of all Treg cells as such its important to describe it here. However
CD4+CD25hiCD127low/-elevated IFN- and IL-21 secretion, and it acted a cell-to-cell contact-dependent manner and depended on IL-6 secretion [65]. And activated by three main pathways STAT5, PI3K/Akt/mTOR and MEK/Erk [49]. There is evidence suggesting that CD4+CD25hiCD127low/-host cells are major targets of anti-CD127 that modulate therapeutic CD8+ T cell responses and the outcome of anti-CD127 -assisted [66]. How treatment is carried out by blockade of PD-1+ and Tim-3+ inhibition as a synergistic effect on IFN- secretion [41] blockades of Notch signaling inhibits suppression function of CD127dim/-in gastric cancer [40].
The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate and adenosine diphosphate to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer-cell responses thereby suppressing the immune system [69]. The CD39+ the suppress anti-tumor immune response via the adenosine-mediated pathway but independent of TGF- or IL-10 and secrete IL-17A and GM-CSF.

CD4+LAP+ Treg-mediated suppression of anti-tumor immune response
The latency-associated peptide (LAP) is a recently discovered subset of CD4+ Treg cells. LAP+ Treg cells accumulate in the tumor microenvironment of colorectal cancer, were elevated in liver metastasis from colorectal cancer [81]. It is present as clusters in the tumor stroma of patients with hepatocellular carcinoma [82] in tumor-infi ltrating B-cells [83] and gastric carcinoma [60]. And it is 50-fold more potent immunosuppressive ability than traditional CD4+CD25+ T cells [84], The anti-LAP suppresses anti-tumor immune response through IL-10, TGF- [84]. IL-10 in liver metastasis [61,85] Anti-LAP antibody targets the LAP/TGF- complex on Treg to enhance immune responses and reduces tumor growth by increasing the infi ltration of tumors by cytotoxic CD8+ T cells [83]. Anti-LAP decreases LAP+ Tregs, tolerogenic dendritic cells and TGF- secretion, and is associated with CD8+ T cell activation, with increased expression of CTLA-4 and IL-10 and decreased expression of IFN-, TNF-, and granzymes. 79 85 Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy [83]. LAP+CD4+ T cells showed lower Foxp3 expression but signifi cantly higher levels of CTLA-4, CCR4, and CCR5 [81].
Furthermore, within the HCC tissues, LAP CD4 T cells were a gift as clusters within the neoplasm stroma and closely related to CD4 T lymphocytes in contrast, within the peri-cancer liver tissues and HBV-infected viscus tissues around benign lesions LAP, CD4 T cells sparsely distributed [83]. LAP+CD4+ T cells have anti-tumor suppressive effects within the peripheral blood of neoplasm tissues, and it is a factor in the suppression of anti-tumor immunity in the neoplasm cells [83]. Anti-LAP antibodies inhibit the discharge, inhibit neoplasm growth in mouse models [84] and have promise as a novel cancer medicine the situation of the LAP-TGF1 advanced is of crucial biological, clinical importance, once the mature TGF1 protein, is free, it acts domestically, either in associate degree autocrine or close to paracrine fashion [85]. These results warrant additional analysis to work out the effectiveness of anti-LAP in inhibiting the discharge and its effects on immunological disorder within the neoplasm microenvironment [86]. They compared the suppressive activity of CD4+CD25+ regulatory T cells (conventional Treg) with T cells expressing T cell immunoglobulin-3+ (TIM3+) and latencyassociated peptide (LAP)+ T cells [87]. They found that LAP-expressing T cells were more suppressive than conventional Treg, but TIM-3expressing T cells were not suppressive [88].