FCGR1A (CD64) is a 72-kDa transmembrane glycoprotein with CD32 and CD16 receptors (Kiyoshi et al., 2015; Lu and Sun, 2015). It encodes a protein that plays an important role in both innate and adaptive immune response. The protein is a high-affinity Fc-gamma receptor. FCGR1A is one of three related gene family members located on chromosome 1 and often expressed on the surface of monocytes, macrophages, and dendritic cells (DCs) (Hulett and Hogarth, 1998). However, CD64 is rarely expressed on the surface of neutrophils (PMN) in normal condition. When the body is infected, CD64 expression on the surface of neutrophils can be rapidly increased under the stimulation of bacterial lipopolysaccharide, interleukin-12, interferon-γ, and granulocyte colony-stimulating factor (Mangalam and Yadav, 2019). Neutrophils are often the first immune cells to reach sites of infection, and their main function is to phagocytose and destroy invading microorganisms or foreign material. Increased CD64 expression is one of the markers of PMN activation and can be used as a good diagnostic indicator of infectious diseases (Cid et al., 2010). Previous studies have reported that FCGR1A (CD64) is of great significance for diagnosis of leukemia (Kern et al., 2006). Acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) are both subtypes of AML, which significantly correlated with the expression of CD64 (Thepen et al., 2009).

Cervical cancer is the fourth most common cancer among women worldwide, with a high mortality rate, especially in developing countries (Bray et al., 2018). High-risk types of human papillomavirus (HPV) infections are strongly associated with a high incidence of cervical cancers; thus, HPV vaccination and screening are necessary (Crosbie et al., 2013). Immunotherapy brings hope for women with recurrent and metastatic cervical cancer (Cohen et al., 2019). Cholangiocarcinoma (CHOL) is an epithelial cell malignancy arising from diverse anatomic locations within the biliary tree, which is classified as intrahepatic, perihilar, and distal CHOL based on anatomical location (Razumilava and Gores, 2014). CHOL accounts for approximately 3% of all gastrointestinal malignancies, and the diagnosis and treatment remain extremely difficult (Khan et al., 2019). Several studies have pointed out that M2 macrophage polarization correlates with poor prognosis and metastasis of CHOL (Hasita et al., 2010; Thanee et al., 2015; Kaneda et al., 2016). Tumor-associated macrophages (TAMs) and tumor-associated neutrophil infiltration are positively associated with poor clinical outcomes, but they have not yet been considered as a therapeutic target for CHOL (Shen et al., 2014; Lee et al., 2016; Tan et al., 2016). Kidney renal clear cell carcinoma (KIRC) is the most common subtype of renal cell carcinoma (80%), and nearly 25% of patients were diagnosed at an advanced stage with lymphatic or distant metastasis (Sinha et al., 2017; Zhang B. et al., 2019). Several reports have indicated that high expression of CTLA4, LAG3, and TIGIT is related to a worse overall survival (OS), whereas high expression of TIM-3 is associated with better prognosis (Zhang S. et al., 2019). Programmed death-1 (PD-1) inhibitors (nivolumab) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC. CTLA-4 (ipilimumab) and PD-1 ligand inhibitors (avelumab) are currently under study (Barata and Rini, 2017). Skin cutaneous melanoma (SKCM) is one of the most aggressive cancers, accounting for 4% of all skin cancer types but 75% of skin cancer–related deaths because of its high metastatic potential (Shenenberger, 2012). The checkpoint inhibitors nivolumab (Olbryt, 2019) and pembrolizumab (Bardhan et al., 2016) have been approved by the FDA for advanced melanoma patients and have yielded a superior overall response rate (Olbryt, 2019).

In this study, we comprehensively analyzed the relationship between the expression of FCGR1A and prognosis of various cancer types using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Besides, Tumor Immune Estimation Resource (TIMER) was utilized to study the correlation between FCGR1A and tumor-infiltrating immune cells. We also elaborated the important role of FCGR1A in cervical and endocervical cancer (CESC), CHOL, KIRC, and SKCM, as well as revealing a potential relationship among FCGR1A, tumor–immune interactions, and neighboring genes.

FCGR1A (CD64) is the single high-affinity receptor of immunoglobulin G (IgG) in human. The expression of FCGR1A is closely related to immune inflammation. Although there are few extensive and systematical studies about CD64, its high sensitivity and specificity for the diagnosis of sepsis and systemic infection had been demonstrated, with a sensitivity of greater than 90% and specificity of 90–100% in adults and children (Hoffmann, 2009). Besides, elevated CD64 had been reported as a potential biomarker for the diagnosis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome (Yamazaki et al., 2014). FCGR1A is the encoding gene of CD64, and the up-regulation of FCGR1A leads to high expression of CD64. CD64 plays an important role in resistance to pathogen invasion through antibody-dependent cell-mediated cytotoxicity (ADCC), cell phagocytosis, and clearance of immune complexes. In normal conditions, CD64 is mainly expressed in monocytes, macrophages, and DCs but lower expression in neutrophils and lymphocytes. When the body or cells are stimulated by endotoxin or immune factors, the expression level of CD64 in the neutrophils increases, and FCGR1A is up-regulated. Here, we studied the association between FCGR1A and the prognosis of different cancers. High expression of FCGR1A exhibited a superior survival in CESC, CHOL, and SKCM, but associated with a poor prognosis in KIRC. Moreover, our research showed that immune infiltration levels and various immune marker genes were closely related to the FCGR1A expression levels. Thus, we can infer that FCGR1A can be regarded as a potential biomarker of cancers and play a role in tumor immunology.

We explored the expression levels of FCGR1A in 33 cancer types using TCGA data in GEPIA. The significant differential expression of FCGR1A was observed in many cancer types. In contrast to the normal tissue, FCGR1A expressed highly in BLCA, BRCA, CESC, CHOL, COAD, ESCA, GBM, HNSC, KIRC, KIRP, LAML LGG, OV, PAAD, PRAD, READ, SKCM, STAD, TGCT, THCA, UCEC, and UCS, but lowly in LUAD, LUSC, and THYM. Moreover, FCGR1A expression levels were significantly correlated with the OS of CESC, CHOL, KIRC, and SKCM and had notable differences between tumor and normal tissues in these four cancers. Besides, FCGR1A expression in KIRC and SKCM showed conspicuous discrepancies at different stages. Taken together with the above results, FCGR1A was strongly confirmed as a prognostic biomarker in CESC, CHOL, KIRC, and SKCM.

This study also indicated that FCGR1A was associated with multiple levels of immune infiltration in cancers. FCGR1A had the strongest correlation with DCs among six tumor-infiltrating immune cells in CESC, KIRC, and SKCM. It had higher relevancy with neutrophils in CHOL as well. Furthermore, significant positive relevance between FCGR1A expression and six immune cells was discovered in four cancers. CD3E, CD2, CD86, CD163, VSIG4, MS4A4A, HLA-DPB1, HLA-DRA, HLA-DPA1, and TIM-3 were found to be mainly gathering in T cells, monocytes, macrophages, and DCs were significantly correlated with FCGR1A. Similar results were validated in GEPIA. Therefore, the association of FCGR1A with diverse immune cell marker genes suggested its role in regulating tumor immunology in CESC, CHOL, KIRC, and SKCM. M1 macrophage gene markers (such as NOS2 and IRF5) had weak or no correlation with FCGR1A expression, while M2 macrophage markers CD163, VSIG4, and MS4A4A had strong correlations. These consequences indicated the potential regulatory role of FCGR1A in the polarization of TAMs. The increased expression of FCGR1A was positively correlated with the expression of Tregs and T cell exhaustion markers (FOXP3, CCR8, PD-1, Tim-3, and LAG3), suggesting that FCGR1A may play a role in the activation of Tregs and induction of T cell exhaustion. The FCGR1A was moderately or strongly associated with most immune marker genes in DCs, which can induce immune memory responses in cancer and promote anti-tumor immunity. Thus, the relationship between FCGR1A expression and the infiltration level of DCs may predict the prognosis of the disease and the response to therapies. TIM-3 is a vital surface protein on T cell exhaustion (Huang et al., 2015) and is highly correlated with FCGR1A expression in CESC and SKCM. Literature had reported that patients with high expression of TIM-3 had high metastatic potential, advanced cancer grades, and shorter OS than those with low expression in cervical cancer (Cao et al., 2016). And some studies had pointed out that TIM-3 is an immunomodulatory molecule in melanoma cells (Wiener et al., 2007). Besides, FCGR1A was positively correlated with T helper cells (such as T_H1) and may be involved in the regulatory role of T cells. Taken together, FCGR1A plays a crucial role in the activation and regulation of immune cells in CESC, CHOL, KIRC, and SKCM based on the above evidence.

To have a better understanding of FCGR1A, GO enrichment and KEGG pathway analysis was carried out. FCGR1A was involved in various biological process, molecular function, and cellular component, which mainly includes Fc receptor signaling pathway, immune response–regulating cell surface receptor signaling pathway, phosphotyrosine residue binding, immunoglobulin binding, plasma membrane, whole membrane, etc. KEGG analysis was used to identify significant signaling pathways. Among its related pathways, Fc gamma R–mediated phagocytosis and osteoclast differentiation were the most important. According to the PPI network and correlation score, FCGR3A, SYK, and HCK were the most relevant neighboring genes. FCGR3A (low-affinity immunoglobulin gamma Fc region receptor III-A) was the receptor for the Fc region of IgG and bound complexed or aggregated IgG and monomeric IgG. It mainly mediated ADCC and other antibody-dependent responses (Mahaweni et al., 2018). SYK was a non-receptor tyrosine kinase, which mediates signal transduction downstream of transmembrane receptors including classical immunoreceptors (Mócsai et al., 2010). HCK was found in hematopoietic cells that transmitted signal from cell surface receptors and regulated innate immune responses. It also acted downstream of receptors that bound the Fc region of immunoglobulins, such as FCGR1A, FCGR2A, CSF3R, etc. (Yang et al., 2016). These three genes were all demonstrated to be associated with various cancer types or drug responses (Fueyo et al., 2018; Magnes et al., 2018; Roseweir et al., 2019). Our findings also confirmed that FCGR3A had highly significant positive associations with FCGR1A in four cancers. This evidence may help us infer the correlation between FCGR1A and cancers. In addition, we sought to investigate the relationship between FCGR1A and some genes that were confirmed to be related to cancers. Here, we took CASS4 (HEPL) as an example. CASS4 (Cas scaffold protein family member 4) was a protein coding gene and played a role in tyrosine kinase-base signaling related to cell adhesion and cell spreading, as well as regulating PTK2/FAK1 activity and focal adhesion integrity (Singh et al., 2008). The published research showed that CASS4 overexpression increased cell spreading and FAK activation. And it may be most in connection with the normal function of lung and hematopoietic system. We explored the correlation between FCGR1A and CASS4 in various cancer types through TIMER database. The results indicated that FCGR1A and CASS4 showed positive correlations in all cancer types including the four cancers we studied (P < 0.05, ρ > 0) (Supplementary Figure 2). Meanwhile, genemania⁴ was used to construct the PPI network (Supplementary Figure 3). Although there was no direct correlation between CASS4 and FCGR1A, these two genes were both associated with CD68, CCR1, CD300C, LILRA5, and PLEKHS1. The underlying mechanisms for gene-specific interplay among these two genes may be worthy of further investigation.

Several studies on FCGR1A (CD64) mainly focused on the diagnosis and distinction of infectious diseases, but rarely on cancer. However, an experimental study published in 2013 pointed out that FcRI (CD64) could mediate the protective effect of anti-tumor antibodies on melanoma metastasis and may also have a protective effect on solid tumors (Mancardi et al., 2013). In addition, CD64 is often used in combination with C-reactive protein (CRP), procalcitonin (PCT), and other inflammatory markers for diagnosis (Yeh et al., 2019). Multiple studies have demonstrated the predictive value of CRP in cancer outcomes. They showed that CRP was generally 1.3-fold higher than normal level in all cancer types. In lung cancer, CRP displayed more than 2-fold higher than normal value and increased approximately 80% risk of early mortality (Allin and Nordestgaard, 2011). Moreover, elevated CRP at diagnosis was associated with poor prognosis in breast cancer (Allin et al., 2011). A study proposed that PCT was closely related to the diagnosis and outcome of lung cancer (Pardo-Cabello and Manzano-Gamero, 2019). Therefore, infectious indicators are also of great value in cancer diagnosis and prognosis prediction and might be a novel promising biomarker. However, at present, insufficient information is available about FCGR1A; further experimental and clinical studies should be conducted to validate our findings.

In summary, high FCGR1A expression leads to different outcomes in diverse cancers. It is associated with better prognosis in CESC, CHOL, and SKCM besides CHOL. Meanwhile, FCGR1A is positively or even strongly correlated with immune cells and various immune cell marker genes in four cancer types, such as CD2, CD3E, CD86, CD163, VSIG4, MS4A4A, HLA-DPB1, HLA-DRA, HLA-DPA1, ITGAX, and TIM-3 in T cell, monocyte, M2 macrophage, DC, T_H1, and T cell exhaustion. Thus, FCGR1A may contribute to the activation and regulation of the aforementioned immune cells to varying degrees. FCGR1A may play an important role in immune cell infiltration and serve as a prognostic biomarker for four cancers, especially in SKCM. Also, FCGR1A is involved in many pathophysiological processes and is closely related to FCGR3A, SYK, and HCK in various cancers. It seems that many questions need to be addressed by future research.

Publicly available datasets were analyzed in this study. This data can be found here: http://gepia2.cancer-pku.cn/#general and https://cistrome.shinyapps.io/timer/.

J-lX: conceptualization, formal analysis and investigation, and writing-original draft preparation. YG: conceptualization, methodology, writing-review and editing, and supervision. Both authors contributed to the article and approved the submitted version.

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.