LSCC, a most common tumor of head and neck , is prone to recurrence and metastasis. Patients who suffer from recurrent or metastatic LSCC and those with a poor response to platinum-based chemotherapy have a low survival rate . Since the immune system plays a vital role in cancer development, immunotherapy is now extensively applied to counteract the immune escape against malignant cancer cells through regulating the key signaling pathways in the host immune system. In particular, cancer immunotherapy shows potentials of durable responses with fewer adverse effects than conventional treatments . The first cancer immunotherapy drug approved by the Food and Drug Administration (FDA) in 2011 was ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA4)-blocking monoclonal antibody (mAb) for metastatic melanoma.
Although the prognostic models of LSCC for predicting overall survival are constantly updated [23, 24], immune-related prognostic index models of LSCC have rarely been reported. In this study, we first identified 371 up-regulated and 61 down-regulated IRGs of LSCC, and the prognostic IRGs were subsequently screened out. Through establishing a prognostic index model, LSCC patients were classified into the high-risk and the low-risk groups. Our findings demonstrated the great performance of the prognostic index model in predicting the prognosis of LSCC patients as revealed by the ROC curves.
To further explore the biological functions of IRGs in the development of LSCC, pathway enrichment analysis was conducted to depict the regulatory network. The KEGG analysis showed that prognostic IRGs were mainly enriched in the cytokine-cytokine receptor interaction. Immune cells and a network of pro-inflammatory and anti-inflammatory cytokines collaborate in cancer development and progression. Cytokines are a heterogeneous group of soluble, small polypeptides or glycoproteins involved in virtually every aspect of immunity and inflammation . It is believed that an environment rich in inflammatory cells, cytokines and activated stroma potentiates and/or promotes neoplastic risk . Our study also found that the relationships between TFRC, PPARG, AHNAK, TRBC1 and their surrounding TFs were more complex in the regulatory network. TFRC is differentially expressed in tumors[28, 29]. PPARG is considered as a prognostic marker[30, 31]. Our results confirmed that AHNAK acted as a potential tumor suppressor and could be a reliable clinical prognostic indicator[32, 33]. Nevertheless, the potential role of TRBC1 in cancer development remains unclear.
In the constructed prognostic model, the following IRGs were subjected to the calculation of risk score: RBP1, TLR2, PAEP, AHNAK, AQP9, CCL2, PPARG, CYSLTR2, FPR2, BTC, EPO, STC2, TNFRSF4, FCGR3B, PLCG1, AHNAK and PPARG. More frequent methylation of RBP1 is found in the esophageal squamous cell carcinoma than in the normal esophagus . TLR2 may be relevant to susceptibilities of oral squamous cell carcinoma and oral lichenoid lesions. Aquaporins (AQPs), a family of small membrane transport proteins, assist the transportation of water and small solutes such as glycerol . It has been reported that AQP9 is up-regulated in human glioma tissues . In astrocytoma, AQP9 promotes cancer cell invasion and motility via the AKT pathway . Ferreira et al. suggested that CCL2 promoted the spread of oral cavity squamous cell carcinoma to lymph nodes and the macrophage infiltration might play a role in less aggressive behaviors . Cysteinyl-LTs participate in the pathogenesis of several chronic inflammatory diseases . Previous studies found that FPR2-induced paracrine might contribute to the proliferation and metastasis of LSCC , which is consistent with our findings. Betacellulin (BTC), a member of the EGF family, acts as a potent mitogen for various cell types. BTC is frequently reported to be up-regulated in human tumors [43–45]. Seibold ND et al. demonstrated that EPO expression in locally advanced squamous cell carcinoma of the head and neck was an independent prognostic factor for locoregional control, metastases-free survival and overall survival. Protein level of STC2 in tumor tissues is associated with invasiveness in the thyroid cartilage, T-stage, lymph node metastasis, clinical stage and pathological differentiation of LSCC. In addition, protein level of STC2 is an independent prognostic factor for overall survival of LSCC [47–49]. Zhu et al. suggested that phospholipase C gamma 1 (PLCG1) could be used as a prognostic biomarker for patients with advanced oral squamous cell carcinoma. So far, the involvement of PAEP, TNFRSF4 and FCGR3B in LSCC or head and neck tumors remains unclear, which requires further exploration.
T cells contribute to oncological immune defense and B cells basically belong to the adaptive immune system. Currently, most immunotherapies are based on T cells . In this study, we found that B cells were significantly enriched in the low-risk group compared to the high-risk group, suggesting that B cell infiltration might be a good prognostic signal for LSCC patients. B lymphocytes are the effector cells of humoral immunity and can terminally differentiate into antibodies that secrete plasma cells upon stimulation. Moreover, B cells contribute to cellular immunity by acting as antigen-presenting cells (APCs) and/or providing costimulatory signals to T cells [52, 53]. The role of B lymphocytes in tumor immunity is still controversial. On the one hand, antigen-presenting B cells are able to activate tumor-specific cytotoxic T cells . B cell deficient mice exhibit significantly reduced tumor-specific T cell immunity . On the other hand, B cell antibody response may potentiate chronic inflammation and thus enhance tumor development [56, 57]. It is reported that tumor infiltrating B-cells are correlated with a good prognosis for head and neck cancer , which is consistent with our findings.
There are still some deficiencies in our study. First of all, we constructed a unique prognostic model of LSCC by analyzing IRGs. However, in-depth analyses on clinical data of LSCC patients are needed to confirm our findings. Secondly, we did not monitor the relative expressions of the selected 15 IRGs in LSCC patients to assess their prognostic values. Thirdly, in vivo and in vitro functional experiments are needed to further validate our findings.