Abstract

Introduction

   Immune checkpoint inhibitors (ICIs) have shown promising results for
   the treatment of multiple cancers. ICIs and related therapies may also
   be useful for the treatment of thyroid cancer (TC). In TC, Myc binding
   protein 2 (MYCBP2) is correlated with inflammatory cell infiltration
   and cancer prognosis. However, the relationship between MYCBP2
   expression and ICI efficacy in TC patients is unclear.

Methods

   We downloaded data from two TC cohorts, including transcriptomic data
   and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion
   (TIDE) algorithm was used to predict the efficacy of ICIs in TC
   patients. MCPcounter, xCell, and quanTIseq were used to calculate
   immune cell infiltration scores. Gene set enrichment analysis (GSEA)
   and single sample GSEA (ssGSEA) were used to evaluate signaling pathway
   scores. Immunohistochemical (IHC) analysis and clinical follow up was
   used to identify the MYCBP2 protein expression status in patients and
   associated with clinical outcome.

Results

   A higher proportion of MYCBP2-high TC patients were predicted ICI
   responders than MYCBP2-low patients. MYCBP2-high patients also had
   significantly increased infiltration of CD8+ T cells, cytotoxic
   lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic
   cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients
   had higher expression of genes associated with B cells, CD8+ T cells,
   macrophages, plasmacytoid dendritic cells (pDCs), antigen processing
   and presentation, inflammatory stimulation, and interferon (IFN)
   responses. GSEA and ssGSEA also showed that MYCBP2-high patients had
   significantly increased activity of inflammatory factors and signaling
   pathways associated with immune responses.In addiation, Patients in our
   local cohort with high MYCBP2 expression always had a better prognosis
   and greater sensitivity to therapy while compared to patients with low
   MYCBP2 expression after six months clinic follow up.

Conclusions

   In this study, we found that MYCBP2 may be a predictive biomarker for
   ICI efficacy in TC patients. High MYCBP2 expression was associated with
   significantly enriched immune cell infiltration. MYCBP2 may also be
   involved in the regulation of signaling pathways associated with
   anti-tumor immune responses or the production of inflammatory factors.

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

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 ([41]1, [42]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 ([43]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 ([44]4–[45]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 ([46]9,
   [47]10). At present, Programmed Cell Death-Ligand 1 (PD-L1) expression
   and tumor mutation burden (TMB) are the main markers of ICI
   effectiveness ([48]9–[49]12). However, these biomarkers also have some
   disadvantages: thresholds of TMB are different across studies, and
   PD-L1 detection platforms vary ([50]13–[51]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 ([52]17).
   Previous studies have shown that MYCBP is associated with the
   occurrence and prognosis of lung cancer, gastric cancer, breast cancer,
   and glioma ([53]18–[54]20). Pierre et al. found that MYCBP2 expression
   was associated with an M2-like macrophage phenotype in a mouse model
   ([55]21). Schaid et al. found that MYCBP2 expression was associated
   with an elevated risk of invasive prostate cancer ([56]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 ([57]GSE138042-THCA) with transcriptomic
   data from the GEO database ([58]https://www.ncbi.nlm.nih.gov/geo/)
   ([59]23). We also downloaded another THCA cohort (TCGA-THCA) with gene
   expression profile data from TCGA database
   ([60]https://portal.gdc.cancer.gov/) ([61]24). Because the public
   databases did not publish data on the efficacy of ICIs by THCA, we used
   the TIDE algorithm ([62]http://tide.dfci.harvard.edu) ([63]25). The
   transcriptomic data from [64]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 ([65]26) and an ICI-treated
   urothelial cancer (UC) ([66]27) cohort, including transcriptomic data
   and prognostic data from the cbioportal webtools
   ([67]https://www.cbioportal.org/) ([68]28). Also, we downloaded two
   datasets related to the mice model treated with the ICIs [[69]GSE146027
   ([70]29) and [71]GSE151829 ([72]30)]. We downloaded the expression data
   and survival data of different cancer types [[73]GSE26304 ([74]31),
   [75]GSE1456 ([76]32), [77]GSE5327 ([78]33), [79]GSE30929 ([80]34),
   [81]GSE26939 ([82]35), [83]GSE30219 ([84]36), [85]GSE41271 ([86]37),
   [87]GSE30219 ([88]36), [89]GSE37745 ([90]38), [91]GSE50081 ([92]39),
   [93]GSE62452 ([94]40), and [95]GSE16560 ([96]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 ([97]http://camoip.net/)
   ([98]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
   ([99]43–[100]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) ([101]https://www.kegg.jp/), Reactome
   ([102]https://reactome.org/), Gene Ontology- Biological Process
   (GO-BP), Gene Ontology- Cellular Component (GO-CC), and Gene Ontology-
   Molecular Function (GO-MF) databases ([103]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
   ([104]http://www.gsea-msigdb.org/gsea/downloads.jsp) ([105]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 ([106]Figure 1A). In the
   [107]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) ([108]Figure 1B, P <
   0. 05). MYCBP2-high patients in TCGA-THCA cohort also had a higher
   predicted response rate to ICIs ([109]Figure 1C, 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 ([110]Figures 1D, E). [111]Figure 1D shows that MYCBP2-high
   melanoma patients had significantly longer OS time than MYCBP2-low
   patients (log rank P = 0. 019, HR = 0. 3). [112]Figure 1E 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 ([113]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
   ([114]Supplementary Table 1, [115]Supplementary Figure 2).

Figure 1.

   [116]Figure 1
   [117]Open in a new tab

   The association between the MYCBP2 expression and ICI efficacy. (A) The
   overall design of the study. The differences in predicted ICI efficacy
   between the MYCBP2-High and MYCBP2-Low TC patients in the
   [118]GSE138042-TC (B) and TCGA-THCA (C) cohorts. KM curve showing the
   differences in the prognoses of ICI-treated patients between the
   MYCBP2-High and MYCBP2-Low groups in the melanoma (D) and urothelial
   cancer (E) cohorts. (*: P < 0.05).

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 ([119]Figure 2A, P < 0.
   05). In the [120]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
   ([121]Figure 2B). In the TCGA-THCA cohort, these genes were expressed
   at significantly higher levels in MYCBP2-high patients than in
   MYCBP2-low patients ([122]Supplementary Figure 3).

Figure 2.

   [123]Figure 2
   [124]Open in a new tab

   The association between the MYCBP2 expression and immune-related gene
   expression. (A) Differences in the expression of immune checkpoint
   molecules between MYCBP2-High and MYCBP2-Low patients in the
   [125]GSE138042-TC cohort. (B) Heatmap depicting differences the
   expression of immune-related genes (antigen presentation, B cells, CD8+
   T cells, macrophages, NK cells, pDCs, stimulation, and IFN responses)
   between MYCBP2-High and MYCBP2-Low patients in the [126]GSE138042-TC
   cohort. (*: P < 0.05; ***: P < 0.001; ****: P < 0.0001).

Relationship between MYCBP2 expression and immune cell infiltration

   We used the MCPcounter algorithm to evaluate immune cell infiltration
   in the TIME of THCA patients ([127]Figures 3A, B). In both the
   [128]GSE138042-THCA ([129]Figure 3A) and TCGA-THCA ([130]Figure 3B)
   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 ([131]Figures 3C, D). Using the
   quanTIseq algorithm, we found that MYCBP2-high patients had
   significantly enriched B cells, NK cells, and DCs ([132]Figure 3C:
   [133]GSE138042-THCA; [134]Figure 3D: TCGA-THCA, all P < 0.05). We also
   used the xCell algorithm to evaluate the proportions of tumor
   infiltrating immune cells ([135]Figures 3E, F). 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 ([136]Figure 3E:
   [137]GSE138042-THCA; [138]Figure 3F: TCGA-THCA).

Figure 3.

   [139]Figure 3
   [140]Open in a new tab

   The association between the MYCBP2 expression and immune cell
   infiltration. Differences in tumor infiltrating immune cells estimated
   by MCPcounter, between the MYCBP2-High and MYCBP2-Low TC patients in
   the [141]GSE138042-TC (A) and TCGA-THCA (B) cohorts. Differences in
   tumor infiltrating immune cells estimated by quanTIseq, between the
   MYCBP2-High and MYCBP2-Low TC patients in the [142]GSE138042-TC (C) and
   TCGA-THCA (D) cohorts. Differences in tumor infiltrating immune cells
   estimated by xCell, between the MYCBP2-High and MYCBP2-Low TC patients
   in the [143]GSE138042-TC (E) and TCGA-THCA (F) cohorts. (ns: not
   significant; *: P < 0.05; **: P < 0.01; ***: P < 0.001; ****: P <
   0.0001).

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 ([144]Figure 4A:
   [145]GSE138042-THCA; [146]Figure 4B: 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 ([147]Figure 4C:
   [148]GSE138042-THCA; [149]Figure 4D: 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
   ([150]Figure 4E: [151]GSE138042-THCA; [152]Figure 4F: 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 ([153]Figure 4E: [154]GSE138042-THCA;
   [155]Figure 4F: TCGA-THCA, P < 0. 05).

Figure 4.

   [156]Figure 4
   [157]Open in a new tab

   The association between the MYCBP2 and immune-related signaling
   pathways. Differences in inflammatory molecule related signaling
   pathways between MYCBP2-High and MYCBP2-Low TC patients in the
   [158]GSE138042-TC (A) and TCGA-THCA (B) cohorts. Differences in immune
   response related signaling pathways between the MYCBP2-High and
   MYCBP2-Low TC patients in the [159]GSE138042-TC (C) and TCGA-THCA (D)
   cohorts. Barplot showing the differences in ssGSEA scores between the
   MYCBP2-High and MYCBP2-Low TC patients in the [160]GSE138042-TC (E) and
   TCGA-THCA (F) cohorts.

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 ([161]Figure 5).

Figure 5.

   [162]Figure 5
   [163]Open in a new tab

   IHC analysis of MYCBP2 expression and clinical follow up of TC patients
   based on their MYCBP2 expression status.Here, we show four representive
   IHC results of patients and corresponding ultrasound follow-up image.

Discussion

   Compared to conventional chemotherapy, ICIs has higher safety and fewer
   adverse reactions, making it a useful treatment regimen for various
   advanced cancers ([164]48). ICIs is now a potential treatment for
   patients with advanced and refractory TC ([165]49–[166]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 ([167]52). CD8 + T cells can kill target cells in an
   antigen-specific manner, and improve the disease-free survival (DFS)
   rate of patients ([168]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 ([169]54). NK cells also
   release lysosomes containing perforin and granzyme to kill target cells
   ([170]55). Many studies have also shown that DCs are a key regulatory
   factor for the efficacy of ICIs and other tumor immunotherapies
   ([171]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 ([172]51, [173]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 ([174]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 ([175]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 ([176]60), and the
   combination of IL-12, IL-15, and IL-18 can increase memory NK cells and
   stimulate IFN-γ secretion ([177]61, [178]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 ([179]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 ([180]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 ([181]65,
   [182]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/[183]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.

Funding

   This study was supported by Guangxi Medical and Health Key Cultivation
   Discipline Construction Project.

Conflict of interest

   The authors declare that the research was conducted in the absence of
   any commercial or financial relationships that could be construed as a
   potential conflict of interest.

Publisher’s note

   All claims expressed in this article are solely those of the authors
   and do not necessarily represent those of their affiliated
   organizations, or those of the publisher, the editors and the
   reviewers. Any product that may be evaluated in this article, or claim
   that may be made by its manufacturer, is not guaranteed or endorsed by
   the publisher.

Supplementary material

   The Supplementary Material for this article can be found online at:
   [184]https://www.frontiersin.org/articles/10.3389/fimmu.2022.1048503/fu
   ll#supplementary-material
   Supplementary Figure 1

   The differences of the expression of the Mycbp2 between the
   ICIs-responders and ICIs-non-responders in the [185]GSE146027 (A) and
   [186]GSE151829 (B).
   [187]Click here for additional data file.^ (465.6KB, tif)
   Supplementary Figure 2

   The Kaplan-Meier curves depicting differences in the prognoses of
   cancer patients between the MYCBP2-High and MYCBP2-Low groups
   ([188]GSE26304, [189]GSE1456, [190]GSE5327, [191]GSE30929,
   [192]GSE26939, [193]GSE30219, [194]GSE41271, [195]GSE30219,
   [196]GSE37745, [197]GSE50081, [198]GSE62452, and [199]GSE16560).
   [200]Click here for additional data file.^ (992.8KB, tif)
   Supplementary Figure 3

   Heatmap depicting differences in the expression of immune-related genes
   (antigen presentation, B cells, CD8+ T cells, macrophages, NK cells,
   pDCs, stimulation, and IFN responses) between MYCBP2-High and
   MYCBP2-Low patients in TCGA-THCA.
   [201]Click here for additional data file.^ (9.4MB, tif)
   Supplementary Table 1

   The Kaplan-Meier result of the relationship between the expression of
   MYCBP2 and survival times of the different cancer patients
   ([202]GSE26304, [203]GSE1456, [204]GSE5327, [205]GSE30929,
   [206]GSE26939, [207]GSE30219, [208]GSE41271, [209]GSE30219,
   [210]GSE37745, [211]GSE50081, [212]GSE62452, and [213]GSE16560).
   [214]Click here for additional data file.^ (11.6KB, xlsx)

References