CD 80 and CD 86 Expression, Clinical Implications Are Cancer Dependent as Revealed Through Pan-cancer Analysis

Cluster of Differentiation 80 and CD 86 can also be called B7-1 and B7-2 respectively. They are proteins fundamentally expressed on antigen-presenting cells (APCs), including induced dendritic cells (IDCs), langerhans cells, germinal center dendritic cells (GCDCs), activated monocytes, macrophages and B-cells. They are considered to be a possible therapeutic target and biomarker of great signicance. However, there are still inconsistent pieces of information and their clinical importance is yet to be established.


Abstract Background
Cluster of Differentiation 80 and CD 86 can also be called B7-1 and B7-2 respectively. They are proteins fundamentally expressed on antigen-presenting cells (APCs), including induced dendritic cells (IDCs), langerhans cells, germinal center dendritic cells (GCDCs), activated monocytes, macrophages and B-cells. They are considered to be a possible therapeutic target and biomarker of great signi cance. However, there are still inconsistent pieces of information and their clinical importance is yet to be established.

Methods
Here we investigated CD 80 and 86 as biomarkers by utilizing several large genomic data collections.

Results
This study presented that CD 86 was expressed more in post-treatment blood cancer in the blood and post-treatment blood cancer in the bone marrow while it was expressed least in normal tissues and cell lines. The Hodgkin lymphoma cell line L428 cell lysate illustrated that there was a high relative protein expression of 6.6 for the CD 86 gene. it indicated that cancer in the esophagus had the highest copy number value and indicated a medium level ampli cation of the CD 86 gene and prostate cancer had a hemizygous deletion of the CD 86 gene with the least copy number value. Furthermore, on the non-Hodgkin lymphoma cell line REC1, illustrated the highest relative protein expression of the CD 86 gene among the other types of cancer cell line, its protein expression value was 8.19. Also, for cancer type leukemia, the subtype acute myeloid leukemia showed a signi cant relative protein expression. The acute myeloid leukemia cell line EOL1 indicated that there was a high relative protein expression of 6.5. However, the protein expression for CD 80 is yet to be elucidated.

Conclusions
Taken together, CD 80 ad 86 may be potential biomarkers of great clinical signi cance. The Kaplan Meier plots unveiled that CD 86 and CD 80 were signi cantly associated with overall survival analysis in the Large B-cell lymphoma, and the different tumor types. Background CD 86 (B7.2) gene is essential for transplantation, autoimmunity, and tumor immunity (1,2). CD 86 speci cally functions as a ligand that links two proteins together including the CD 28 antigen and the cytotoxic T-lymphocyte associated protein 4, the joining of CD 86 to CD 28 antigen is a costimulatory signal for the activation of the T-cell (3). Hence, when CD 86 protein is coupled to the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), when this happens the T-cell activation is regulated negatively and the body receives a decreased immune response (4) CTLA-4 is a tremendous endocytic molecule, its residence time on the cell surface is very limited, genes for CD 28 and CTLA-4 are both expressed similarly on the chromosome and they share homology of about 30% at the amino acid level indicating that CD 28 and CTLA-4 have evolved from the same ancestral gene. Whereas CD 28 is constitutively expressed on the surface of most T cells, CTLA-4 expression is limited to activated conventional T cells and more importantly, T-regs thus, high expression of CD 86 proteins (5).
CD 80, which is alternatively called also B7.1, is a coregulatory receptor expressed on the activated T cells, dendritic cells, macrophages, monocytes which are seen on the surface of antigen presenting cells (6, 7). It can also be found on the myeloid-derived suppressor cells (8). Previous investigations unveiled the importance of CD28/B7 family of coregulatory receptors, and that CD 80 is associated with regulation of the immune system (9). Hence, it is capable of enhancing tumor progression in the tumor microenvironment by impeding the immune response of the tumor (4). The expression of CD 86 is low and upregulated quickly on the APC while that of CD 80 is inducibly expressed later than CD 86. The costimulatory molecules on APCs have been investigated extensively meanwhile their functions on the T cells are yet to be elucidated (4).
A biomarker is a biological molecule such as a protein, DNA, RNA, or circulating extracellular vesicles (EVs) that can be found in blood, biological uids and tissues and is an indicator of a normal physiologic or a diseased state, biomarkers are used for molecular diagnosis, patient prognosis and to determine the outcome of the targeted therapy (30). Over the years, cancer researchers have invested their time and resources in the early detection of cancer, however, the diagnosis of cancer has relied on the microanatomy of tissues (31). Cancer researchers have been able to use biomarkers for early detection of tumors, and vigorous research is ongoing to improve the use of biomarkers such as being able to use biomarkers to predict tumor outcome and to predict the response of patients with tumors to particular therapeutic drugs (32). There are various types of biomarkers, which includes diagnostic, prognostic, pharmacodynamic, predictive, safety, and monitor etc (30,32).
Taken together, we utilized the database of The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/), Cancer Cell Line Encyclopedia (CCLE; https://portals. broadinstitute.org/ccle/), DepMap data explorer (http;//depmap.org/portal/interactive), we thoroughly evaluated the expression pattern of CD 80 and CD 86. Hence, we comprehensively analyzed CD 86 and CD 80 as biomarkers of clinical signi cance. We utilized the protein expression, copy number, gene expression, mRNA and survival analysis of different tumor types. To our knowledge, this is the rst investigation to unveil the comprehensive analysis of CD 80 and CD 86 expression and implications are cancer dependent.

Materials And Methods
The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype-tissue expression, Quantitative Proteomic Cancer Cell Line Encyclopedia R-software incorporated into the Xena browser, Human protein atlas, Human proteomics Database were used in the investigation. The investigation was done using a substantial genomic data collection such as The Cancer Genome Atlas, Cancer Cell Line Encyclopedia

DATA PROCESSING AND ANALYSIS
Clinical survival data of lung, lymphoma and leukemia patients from TCGA were downloaded from the database. We utilized the Xena browser in which R software is incorporated. We analyzed our overall survival analysis using Kaplan Meiers plot.

Discussion
The importance of CD 80 and CD 86 in cancer biology and clinical implications have fascinated lots of consideration. Many investigations have been done by the previous researchers however, some of the investigations have the small sample size and there is still inconsistent information and its clinical importance is yet to be established. The expression of CD 86 in different cancer sample types showed that CD 86 was expressed more in post-treatment blood cancer in the blood and post-treatment blood cancer in the bone marrow while it was signi cantly different from expression in cell line and control analyte. Hence, CD 86 may be a possible biomarker in the detection of blood cancer. To comprehend the expression and distribution of CD 86 in normal human tissues, we examined its expression across 19,131 samples from the TCGA TARGET GTEX data. As shown in Fig. 1a, we discovered that the expression of CD 86 in different cancer sample types was signi cantly different from the control analyte P < 0.05. CD 80 gene expression between different cancers and tumor, cell line, control analyte, and their normal tissues were highly dependent on cancer and tumor types. We investigated CD 80 expression on different types of cancer from TCGA Target GTEx. All tumors had a certain level of expression but the expression in primary blood-derived cancer (peripheral blood and bone marrow), was higher than other cancer types (Fig. 1b). Blood cancer (leukemia) have been discovered to have different diagnosis, prognosis and molecular mechanisms (33,34). There are different types of blood cancer which includes myeloid neoplasms, lymphoid neoplasms (leukemias and lymphomas), and myeloproliferative disorders (35) The CD 80 expression in this tumor in the TCGA Target GTEx dataset indicates mRNA expression is an important quantity for CD 80 expression and shows its signi cant role in blood cancer. The P-value (P < 0.05) was signi cantly different from the control analyte. Hence CD 80 may be a potential biomarker for the diagnosis, prognosis and prediction of blood cancer.
Most previous investigations utilized Immunohistochemistry (IHC) to detect CD 86 and CD 80 (36). Protein expression may be determined using the IHC while mRNA expression from RNA may be crucial in the discovery of novel biomarkers (37) and therapeutic targets (38). The correlation between mRNA and protein expression is not fully elucidated. Here, this investigation, utilized the mRNA to unveils the mRNA expression of the CD 80 and CD 86 using the TCGA database. The Burkitt lymphoma was one of the tumors with very high expression of CD 86 mRNA and B-cell lymphoma in CCLE samples; however, its expression was low in lungs (NSCLC), liver, thyroid, ovary, glioma as shown in Fig. 2a. The expression of CD 80 mRNA was high in lymphoma, and Burkitt lymphoma cancer cell lines and was low in urinary tract, thyroid, osteosarcoma, and meningioma cancer cell lines respectively as shown in Fig. 2b. Hence, CD 86 and CD 80 may be useful as biomarker and the expression are in consonant with previous investigations (39) As shown in Fig. 3a, it showed that cancer in the esophagus had the highest copy number value and showed a medium level ampli cation of CD 86 gene and prostate cancer seems to almost have a hemizygous deletion of the CD 86 gene with the least copy number value. The copy number of CD 86 was in a medium ampli cation in lung small cell carcinoma, lung non-small cell carcinoma, B-cell lymphoma and T-cell lymphoma. This indicated that CD 86 was moderately expressed in lung cancer and lymphoma and therefore may be used for detection in lung cancer and lymphoma.
The CD 86 relative protein expression on different cancer cell lines (including the types and subtypes) was investigated. CD 86 relative protein expression on these cancer cell lines as shown in the Fig. 4. Hodgkin lymphoma showed a signi cant relative protein expression. The Hodgkin lymphoma cell line L428 cell lysate illustrated that there was a high relative protein expression of 6.6 for the CD 86 gene meaning that CD 86 may be possible biomarker. Furthermore, on the non-Hodgkin lymphoma cell line REC1 illustrated the highest relative protein expression of the CD 86 gene among the other types of cancer cell line, its protein expression value was 8. 19. Also, for the cancer type leukemia, the subtype acute myeloid leukemia displayed a signi cant relative protein expression. The acute myeloid leukemia cell line EOL1 demonstrated that there was a high relative protein expression of 6.5. however, CD 80 the relative protein expression of different cancer cell lines is yet to be investigated. Furthermore, we used the Kaplan Meier survival analysis to unveil the importance of CD 86 and CD 80 as potential biomarker. From the Kaplan Meier plots, using the different types of tumor from the TCGA and Target Pan Cancer. Hence, the biomarkers were signi cantly associated with overall survival with the different types of tumors. We also used the Large B-cell lymphoma and discovered that the CD 86 and CD 80 were signi cantly associated with overall survival of the patients (Fig. 5a-d). Hence, they may be possible biomarker and therapeutic target (38, 40).

Conclusion And Future Perspective
In conclusion, our analysis unveiled that CD 86 and CD 80 are actually highly expressed in some tumors. The Kaplan Meier survival analysis unveiled that CD86 and CD 80 were signi cantly associated with overall survival analysis in the Large B-cell lymphoma. Hence, they may be potential biomarker of clinical importance in cancer. However, there is need for further investigations in the proteomics of CD 80 which is yet to be elucidated. All the authors contributed in the preparation of this paper. AMO and SIG were responsible for data collection, analysis and drafting of the article. AKO, JAS, OIM, HMR and TJ were responsible for data analysis. AMO and GX made substantial contributions to manuscript conception and design and participated in its critical review and nal editing. All authors read and approved the nal manuscript.    The CD 86 relative protein expression on different cancer cell lines (including the types and subtypes).