MYCBP2 expression correlated with inflammatory cell infiltration and prognosis immunotherapy in thyroid cancer patients

Article type: Research Article

Keywords: immune checkpoint inhibitors, MYCBP2, myc binding protein 2, prognosis, thyroid cancer

Authors: Guilin Wang, Chen Miao, Lijun Mo, Ulf D. Kahlert, Jinfeng Wu, Minglin Ou, Renxiang Huang, Ruifa Feng, Weiyi Pang, Wenjie Shi

Affiliations: Breast Center, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China; Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Molecular and Experimental Surgery,University Clinic for General, Visceral, Vascular and Transplantation Surgery, Faculty of Medicine, Otto-von-Guericke-University, Magdeburg, Germany; Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guilin Medical University, Guilin, Guangxi, China; University Hospital for Gynecology, Pius-Hospital, University Medicine Oldenburg, Oldenburg, Germany

License: Copyright © 2022 Wang, Miao, Mo, Kahlert, Wu, Ou, Huang, Feng, Pang and Shi CC BY 4.0 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Article links: DOI: 10.3389/fimmu.2022.1048503  |  PubMed: 36582246  |  PMC: PMC9792662

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (10.8 MB)

Introduction

Thyroid cancer (TC) originates from follicular epithelial cells or parafollicular epithelial cells of the thyroid. It is the most common malignant tumor in endocrine system and comprises about 90% of endocrine cancers (ref. 1, ref. 2). Although most TCs are relatively inert and can be effectively treated by surgery, radiation,131 and thyroid stimulating hormone (TSH) inhibition therapy, some cases are refractory and eventually lead to disease progression, recurrence, and even death (ref. 3). Although targeted therapies such as kinase inhibitors can prolong patient prognosis, the effectiveness of kinase inhibitors is severely limited due to the rapid development of drug resistance and the occurrence of adverse reactions (ref. 4–ref. 8). In recent years, with increasing use of immune checkpoint inhibitors (ICIs) for anti-cancer therapy, research on the use of ICIs for TC is also rapidly advancing, with the hope of improving the prognosis of TC patients.

Previous research has shown that biomarkers predicting the efficacy of ICIs can help to screen patients and further improve prognoses (ref. 9, ref. 10). At present, Programmed Cell Death-Ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are the main markers of ICI effectiveness (ref. 9–ref. 12). However, these biomarkers also have some disadvantages: thresholds of TMB are different across studies, and PD-L1 detection platforms vary (ref. 13–ref. 16). Therefore, there is need to identify biomarkers that more comprehensively predict the efficacy of ICIs, allowing for the development of tumor precision medicine.

Myc binding protein 2 (MYCBP2) is a E3 ubiquitin ligase (ref. 17). Previous studies have shown that MYCBP is associated with the occurrence and prognosis of lung cancer, gastric cancer, breast cancer, and glioma (ref. 18–ref. 20). Pierre et al. found that MYCBP2 expression was associated with an M2-like macrophage phenotype in a mouse model (ref. 21). Schaid et al. found that MYCBP2 expression was associated with an elevated risk of invasive prostate cancer (ref. 22). However, the relationship between MYCBP2 expression and ICI efficacy in TC remains unclear.

In the present study, we downloaded data on a TC cohort from the Gene Expression Omnibus (GEO) database and a thyroid carcinoma (THCA) cohort from the Cancer Genome Atlas (TCGA) database. We used the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to predict the therapeutic effect of ICIs in TC patients. Next, we evaluated the relationship between MYCBP2 expression and ICI efficacy in TC patients and explored its potential molecular mechanism.

Methods

THCA cohort and ICIs datasets

We downloaded a THCA cohort (GSE138042-THCA) with transcriptomic data from the GEO database (https://www.ncbi.nlm.nih.gov/geo/) (ref. 23). We also downloaded another THCA cohort (TCGA-THCA) with gene expression profile data from TCGA database (https://portal.gdc.cancer.gov/) (ref. 24). Because the public databases did not publish data on the efficacy of ICIs by THCA, we used the TIDE algorithm (http://tide.dfci.harvard.edu) (ref. 25). The transcriptomic data from GSE138042-THCA and TCGA-THCA were used to predict the response of each patient to ICIs, and each patient was categorized as a responder or non-responder. We also downloaded data from an ICI-treated melanoma cohort (ref. 26) and an ICI-treated urothelial cancer (UC) (ref. 27) cohort, including transcriptomic data and prognostic data from the cbioportal webtools (https://www.cbioportal.org/) (ref. 28). Also, we downloaded two datasets related to the mice model treated with the ICIs [GSE146027 (ref. 29) and GSE151829 (ref. 30)]. We downloaded the expression data and survival data of different cancer types [GSE26304 (ref. 31), GSE1456 (ref. 32), GSE5327 (ref. 33), GSE30929 (ref. 34), GSE26939 (ref. 35), GSE30219 (ref. 36), GSE41271 (ref. 37), GSE30219 (ref. 36), GSE37745 (ref. 38), GSE50081 (ref. 39), GSE62452 (ref. 40), and GSE16560 (ref. 41)] to further validate the relationship between the expression of MYCBP2 and the survival time.

Analysis of tumor immune microenvironment

We downloaded the gene set of immune checkpoint (IC) related molecules and immune related molecules from CAMOIP (http://camoip.net/) (ref. 42). We used three immune cell evaluation algorithms (1.MCPcounter, 2.xCell, and 3.quanTIseq) to calculate the immune cell infiltration score of each THCA patient from the expression data (ref. 43–ref. 45).

Pathway enrichment analysis

We used gene set enrichment analysis (GSEA) to analyze the transcriptomic data of THCA patients and obtained pathway enrichment scores and P values of pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) (https://www.kegg.jp/), Reactome (https://reactome.org/), Gene Ontology- Biological Process (GO-BP), Gene Ontology- Cellular Component (GO-CC), and Gene Ontology- Molecular Function (GO-MF) databases (ref. 46). We also applied the single sample GSEA (ssGSEA) algorithm to analyze the transcriptomic data of each THCA patient and then obtained the enrichment scores of each patient in the Molecular Signatures Database (MsigDB) database (http://www.gsea-msigdb.org/gsea/downloads.jsp) (ref. 47).

Immunohistochemical analysis and clinical follow up

To identify the MYCBP2 protein expression status in patients and associated with clinical outcome. We collect tissues samples from thyroid cancer patients,who accepted surgery operation in Breast Center of The Second Affiliated Hospital of Guilin Medical University, to conduct immunohistochemical analysis and follow up six months to evaluate the prognosis difference between high and low expression groups. Thirty-six tissues from twelve patients, each patient has three tissues obtained from different surgery sections, and these tissues were washed with Phosphate-Buffered Saline (PBS) and then incubated with 3% H2O2 for 10 minutes. Samples were incubated with antibody against MYCBP2 (1 mg/mL diluted 1:200, 27951, Proteintech, CA) at room temperature for two hours. After incubation with polymer enhancer for 20 minutes, the tissue was incubated with polymer enhancer and enzyme-labeled rabbit polymers. Slides were washed with PBS and fresh diaminobenzidine and counterstained with hematoxylin; antigen retrieval was performed using 0.1% HCl, and slides were then dehydrated with ethanol, cleaned with xylene, and fixed with neutral balata. The images were observed and photographed using a fluorescence microscope and visualized under a light microscope at 100× magnification by a blinded observer. Light to dark brown staining indicated a positive result from low to high. The stained areas were analyzed using Image J. Patients who donated samples for IHC also accepted clinical follow up to evaluate the association between MYCBP2 expression and patient outcomes following surgery. All patient and tissue studies were approved by the Ethics Committee of Breast Center of The Second Affiliated Hospital of Guilin Medical University.

Statistical analysis

The Mann-Whitney U test was used to compare differences between the MYCBP2-high and MYCBP2-low groups in continuous variables. Fisher’s exact test was used to compare differences between the two groups in categorical variables. Kaplan-Meier curves were used to visualize differences in overall survival (OS) time between the two groups, and a log rank test was used to calculate the difference in OS time. We used the ggplot2 R package to generate boxplots. Visualization and data analysis for the present study were conducted in Rstudio software (Version 4.1.2). P values were bilateral and P values < 0. 05 were considered statistically significant.

Results

Relationship between MYCBP2 expression and ICI efficacy in THCA

In the present study, we explored the relationship between MYCBP2 expression and ICI efficacy in THCA patients and analyzed potential molecular mechanisms for this relationship (f1). In the GSE138042-THCA cohort, MYCBP2-high patients receiving ICIs had a higher proportion of predicted responders than MYCBP2-low patients receiving ICIs (evaluated by the TIDE algorithm) (f1, P < 0. 05). MYCBP2-high patients in TCGA-THCA cohort also had a higher predicted response rate to ICIs (f1, P < 0. 05). Next, we used the ICI-treated melanoma and urothelial cohorts to further verify the relationship between MYCBP2 expression and prognosis in ICI-treated patients (f1). f1 shows that MYCBP2-high melanoma patients had significantly longer OS time than MYCBP2-low patients (log rank P = 0. 019, HR = 0. 3). f1 shows that MYCBP2-high urothelial cancer patients had a significantly longer OS time than MYCBP2-low patients (log rank P = 0. 041; HR = 0. 59, 95% CI: 0. 35-1). In the mice model, we found that the expression of Mycbp2 was significantly increased in the ICIs-responders compared with ICIs-non-responders (Supplementary Figures 1A, B). Also, in the multiple cancer types, we found that MYCBP2-high patients had significantly prolonged survival time compared with MYCBP2-low patients (Supplementary Table 1, Supplementary Figure 2).

Relationship between MYCBP2 expression, IC-related molecules, and immune related genes

In TCGA-THCA cohort, MYCBP2-high patients had significantly higher expression of IC-related molecules, such as LAG3, IDO1, CTLA4, TIGIT, PD-1 and PDCD1LG2, than MYCBP2-low patients (f2, P < 0. 05). In the GSE138042-THCA cohort, the heatmap also revealed differences between MYCBP2-high and MYCBP2-low patients in the expression of genes associated with antigen presentation, B cells, CD8+ T cells, macrophages, pDCs, inflammatory stimulation, and IFN responses (f2). In the TCGA-THCA cohort, these genes were expressed at significantly higher levels in MYCBP2-high patients than in MYCBP2-low patients (Supplementary Figure 3).

Relationship between MYCBP2 expression and immune cell infiltration

We used the MCPcounter algorithm to evaluate immune cell infiltration in the TIME of THCA patients (f3). In both the GSE138042-THCA (f3) and TCGA-THCA (f3) cohorts, MYCBP2-high patients had significantly higher infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, and NK cells than MYCBP2-low patients. The quanTIseq algorithm was also used to verify immune cell infiltration fractions (f3). Using the quanTIseq algorithm, we found that MYCBP2-high patients had significantly enriched B cells, NK cells, and DCs (f3: GSE138042-THCA; f3: TCGA-THCA, all P < 0.05). We also used the xCell algorithm to evaluate the proportions of tumor infiltrating immune cells (f3). Compared with MYCBP2-low patients, MYCBP2-high patients had significantly increased B cells, memory CD4+ T cells, CD8+ T cells, central memory CD8 + T cells (TCMs), and class-switched memory B-cells (f3: GSE138042-THCA; f3: TCGA-THCA).

Relationship between MYCBP2 expression and immune signaling pathways

We found that MYCBP2-high patients had higher activation of immune signaling pathways than MYCBP2-low patients (f4: GSE138042-THCA; f4: TCGA-THCA, ES > 0, P < 0. 05), including pathways regulating cell surface receptor signaling and phagocytosis, Fc receptor signaling, signal transduction, chemokine production, molecular mediators of immune responses, interleukin-12 (IL-12) production, MHC protein complex binding, interleukin-15 (IL-15) signaling, and interleukin-2 (IL-2) family signaling. Signaling pathways related to immune responses and immune cell activation were also significantly upregulated in MYCBP2-high patients, including B cell activation, lymphocyte mediated immunity, leukocyte migration, B cell proliferation, and NK cell mediated cytotoxicity (f4: GSE138042-THCA; f4: TCGA-THCA, ES > 0, P < 0. 05). The results of ssGSEA showed that MYCBP2-high patients had higher immune response pathway scores than MYCBP2-low patients, including pathways for MHC class I protein complex binding, DC cytokine production, MHC class IB receptor activity, IL-12 production, lymphocyte mediated immunity, NK cell mediated cytotoxicity, T cell mediated immunity, interleukin-18 (IL-18) production, NK cell mediated immunity, NK cell activation, DC antigen processing and presentation, and IL-15 signaling (f4: GSE138042-THCA; f4: TCGA-THCA, P < 0. 05). On the contrary, lipid metabolism related pathways (such as short chain fatty acid metabolism, fatty acid beta oxidation using acyl COA oxidase, and positive regulation of vascular permeability) were significantly downregulated in MYCBP2-high patients compared to MYCBP2-low patients (f4: GSE138042-THCA; f4: TCGA-THCA, P < 0. 05).

Validation of the local cohort based on MYCBP2 status

IHC revealed MYCBP2 expression levels in TC tissues. Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy compared to patients with low MYCBP2 expression after six months clinic follow up (f5).

Discussion

Compared to conventional chemotherapy, ICIs has higher safety and fewer adverse reactions, making it a useful treatment regimen for various advanced cancers (ref. 48). ICIs is now a potential treatment for patients with advanced and refractory TC (ref. 49–ref. 51). In this study, we found that higher MYCBP2 expression was associated with better outcomes in TC patients receiving ICIs. Immune cell infiltration analysis showed that higher MYCBP2 expression was associated with significantly enriched inflammatory immune cell infiltration and higher expression of inflammatory molecules. Pathway enrichment analysis showed that MYCBP2 may be involved in anti-tumor immune responses. Therefore, MYCBP2 may be a novel biomarker for ICI efficacy in TC patients.

The significantly enriched inflammatory immune cell infiltration in MYCBP2-high patients is a potential molecular mechanism for the greater efficacy of ICIs in these patients. Bastman et al. found that some TC patients with greater programmed death 1 [PD-1(+)] CD4+ T cell and PD-1(+) CD8+ T cell infiltration could benefit from anti-PD-1/PD-L1 treatment (ref. 52). CD8 + T cells can kill target cells in an antigen-specific manner, and improve the disease-free survival (DFS) rate of patients (ref. 53). NK cells also play a key role in anti-tumor immune monitoring. NK cells can not only kill tumor or infected cells directly, but they can also indirectly enhance antibody and T-cell-mediated anti-tumor immune responses (ref. 54). NK cells also release lysosomes containing perforin and granzyme to kill target cells (ref. 55). Many studies have also shown that DCs are a key regulatory factor for the efficacy of ICIs and other tumor immunotherapies (ref. 56). Accordingly, researchers are now attempting to engineer DCs to activate and drive T cells into the TIME, particularly for tumors with weak immunogenicity (non-inflammatory of “cold” tumors), to improve the efficacy of ICIs (ref. 51, ref. 57). In our study, we found that MYCBP2-high patients had significantly increased CD8+ T cells, B cells, NK cells, and DCs in the TIME compared to MYCBP2-low patients.

The high expression of inflammatory molecules and activation of immune response pathways in MYCBP2-high patients is another potential molecular mechanism for the greater ICI efficacy in MYCBP2-high patients. IL-15 can maintain NK cell populations and tumor killing ability in the TIME (ref. 58). Recently, a clinical trial showed that IL-15 can increase CD8+ T cell and NK cell numbers up to 5.8 and 38 times that of the control group, respectively, and 17 of the 27 patients treated with IL-15 showed no tumor progression (ref. 59). Several other studies have attempted to activate NK cells for immunotherapy using cytokines. For example, IL-21 has been shown to improve the exhaustion status of the NK cells (ref. 60), and the combination of IL-12, IL-15, and IL-18 can increase memory NK cells and stimulate IFN-γ secretion (ref. 61, ref. 62). In our study, we found that MYCBP2-high patients had significantly upregulated IL-12 production, IL-15 signaling, IL-2 family signaling, and IL-18 signaling compared to MYCBP2-low patients.

The pattern of fatty acid metabolism in TME is also crucial in the immunomodulatory function of tumor tissues and immunotherapy tolerance. It has been shown that the expression of genes for fatty acid oxidation is upregulated in Treg and that the level of fatty acid oxidation is increased, thus promoting Treg production (ref. 63). The rate of de novo synthesis of the fatty acid in tumor cells is usually increased, thus shifting energy production to anabolic pathways for the production of plasma membrane phospholipids and signaling molecules (ref. 64). Lipid accumulation in tumor-infiltrating myeloid cells has been shown to predispose these immune cells to an immunosuppressive and anti-inflammatory phenotype through metabolic reprogramming (ref. 65, ref. 66). In our study, we found that lipid metabolism related pathways (such as short chain fatty acid metabolism, fatty acid beta oxidation using acyl COA oxidase, and positive regulation of vascular permeability) were significantly downregulated in MYCBP2-high patients compared to MYCBP2-low patients.

Some limitations are not ignored in our study, first, clinical long-time follow-up was not conducted, and in the future, a more clinical trial should be considered to demonstrate this gene’s clinical value, and in addition, Due to experimental constraints, organoid-related experiments have not been considered, which is a regret, and we hope we will complete this procedure in future cooperation with another excellent laboratory.

Conclusions

In summary, we found that MYCBP2-high TC patients had better responses to ICIs than MYCBP2-low patients, with a higher proportion of predicted ICI responders in the MYCBP2-high group. Higher MYCBP2 expression was associated with significantly enriched inflammatory immune cell infiltration and higher immune response pathway activity.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Ethics statement

The studies involving human participants were reviewed and approved by The Ethics Committee of Breast Center of The Second Affiliated Hospital of Guilin Medical University. The patients/participants provided their written informed consent to participate in this study.

Author contributions

Conceptualization, RF, WP, WS. Formal analysis, GW, CM, LM, UK. Software, GW, CM, LM, UK. Supervision, GW, CM, LM. Resources, GW, CM, LM, UK. Visualization, GW, CM, LM, UK. Writing–original draft, JW, MO, RH. Writing–review & editing, GW, CM, LM, JW, MO, RH, RF, WP, WS. All authors contributed to the article and approved the submitted version.

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