Normal physiological homeostasis is dependent on maintaining a balance between cellular proliferation, death, and differentiation (16). While apoptosis and necrosis were once believed to be the primary forms of cell death, pyroptosis, autophagy, and other mechanisms have also been shown to mediate a loss of cellular viability (27). Pyroptotic cell death is highly inflammatory and plays a role in a variety of pathogenic processes (28–30). Inflammasome activation initiates pyroptosis by recruiting caspase-1. Gasdermin D (GSDMD) serves as a caspase-1/11 substrate, inducing pyroptotic cell death owing to its ability to promote non-selective pore formation within the plasma membrane, subsequently driving cellular swelling, rupture, and the release of proinflammatory factors such as HMGB1, ATP, and IL- 1β (16, 18, 31). The relationship between pyroptosis and cancer is complex, given that this form of cell death can both drive tumor progression and impair antitumor immunity (18), while also inhibiting oncogenesis (32). The mechanisms whereby PRGs affect HNSCC progression and survival outcomes remain to be clarified. Herein, we evaluated expression levels of 31 different PRGs in samples from HNSCC patients in the TCGA database, revealing 21 of these genes to be differentially expressed in HNSCC including 18 that were upregulated in this oncogenic setting. GO and KEGG analyses demonstrated a link between PRGs and cytokine production, IL-1 production, NLRP signaling, and Salmonella infection. These functional pathways were closely associated with HNSCC oncogenesis and progression. Salmonella infection, for example, can promote TLR4/ MyD88 pathway activation and consequent increases in macrophage and neutrophil infiltration (33). In OSCC, targeting of the ROS/NLRP3 inflammasome/IL-1β signaling pathway has been suggested to improve outcomes associated with 5-FU adjuvant chemotherapy (34). These data suggest that in-depth PRG studies may offer improved insight into antitumor immunity and inflammation.
HNSCC patients exhibit poor long-term survival outcomes, underscoring the need for more reliable biomarkers of long-term patient prognosis and treatment outcomes. TNM stage, vascular invasion, and other traditional clinicopathological biomarkers have yielded unsatisfactory outcomes when used to gauge patient prognosis (35). RNA-seq and other high-throughput sequencing technologies have led to the identification of a wide variety of prognostic biomarkers associated with different cancers (36, 37). Recent work has shown individual biomarkers are ill-suited to gauging cancer patient prognosis. A 4-gene immune-related biomarker signature (PVR, TNFRSF12A, IL21R, and SOCS1) may, together with other clinicopathological metrics, offer value as a means of assessing HNSCC patient prognosis (38). Wang et al. assessed patterns of gene expression from 771 HNSCC patients in the TCGA and GEO databases, leading to the development of a 6-gene prognostic risk signature that was able to independently predict patient survival (39). In a similar vein, we herein assessed the prognostic value of PRGs in HNSCC. We ultimately employed a LASSO Cox regression approach to construct a 6-PRG (IL-6, NLRP1, NLRP2, NLRP3, NOD2, and PLCG1) prognostic risk signature. Risk scores derived from this model were able to effectively stratify patients into low- and high-risk cohorts. High-risk patients exhibited worse survival outcomes than did low-risk patients. These findings thus confirm the prognostic value of this novel PRG risk signature, highlighting a novel approach to predicting HNSCC patient outcomes.
Cell death plays a central role in diverse pathological processes (40), with pyroptosis functioning as an inflammatory type of caspase-mediated inflammatory cell death that can modulate the immunogenic potential of specific cancers(41). Such immunogenicity is of critical importance in the context of tumor immunotherapy owing to the ability of tumor cells to activate a variety of immunosuppressive pathways within the local tumor microenvironment (42). Pyroptosis can impact immune cell composition and associated immunological pathway activation to alter the processes governing tumorigenesis. Herein, we compared the immunological status of patients in our low- and high-risk groups, and assessed the relationship between the levels of difference prognostic PRGs in HNSCC (IL-6, NLRP1, NLRP2, NLRP3, NOD2, and PLCG1) and immune cell infiltration. The results of these analyses suggest that this prognostic gene signature may have important implications for immunotherapy treatment planning. Of these genes, only NLRP3 was positively correlated with immune infiltration in the TIMER database. The activation of NLRP3 has previously been reported in the context of metabolic changes, mitochondrial dysfunction, and the disassembly of the Golgi compartment (43). The NLRP3 inflammasome can also promote the caspase-1-dependent release of IL-1β and IL-18, which are inflammatory cytokines, in addition to activating downstream pyroptotic signaling mechanisms (43). Wang et al. observed a positive correlation between NLRP3 expression levels and lymph node metastasis, tumor size, and IL-1β levels in OSCC patients, highlighting this pathway as a promising therapeutic target (44). However, our study showed differences from the previous studies, confirming the dual role of pyroptosis. Based on the cox multivariate regression analysis of NLRP3 in risk model, we noticed that NLRP3 might act as a potential indicator for predicting the HNSCC patients’ outcomes (HR = 0.68, p = 0.039). In line with these reports, the results of our PPI network and survival analyses suggested that NLRP3 may be a valuable predictor of prognosis among HNSCC patients. Lower levels of NLRP3 expression detected via IHC staining were associated with a worse prognosis. Overall, these data demonstrate the value of NLRP3 as a PRG that is independently associated with HNSCC patient survival.