Along with the booming evolution of biotechnological and bioinformatics science, genomic analysis had been widely applied to search cancer biomarkers or develop diagnostic and prognostic models[15, 16]. However, only a few related research focused on the creation of prognostic prediction models for cutaneous melanoma patients. With the help of the Bioconductor in R project, we combined univariate Cox regression and Lasso Cox regression models to screen for PRGs associated with OS, and further developed a prognostic PRG-signature to distinguish patients with different clinical outcomes in the present study. Our study generated an 8 PRGs risk signature (AIM2, CASP4, CASP5, CASP8, IL18, NLRC4, NLRP6, PRKACA) and demonstrated that these regulators OS in patients with cutaneous melanoma. In our present investigation, CASP4, CASP5, and CASP8 appear to be oncogenes that prolong the survival and improve the clinical prognosis of cutaneous melanoma patients maybe through inflammatory and apoptotic pathways respectively. Except for PRKACA, all the other eight PRGs in our study appeared to be suppressants of cancers, which resulted in longer survival times for patients. We created a risk score based on PRG features and discovered that high-risk patients had a worse clinical prognosis and a shorter survival time. The high-risk group had considerably lower scores for immune cell infiltration and immunological pathways than the low-risk group.
Pyroptosis is a type of programmed cell necrosis that has just recently been identified, however, it plays a crucial and dual role in the processes that promote and prevent carcinogenesis. For one thing, pyroptosis can prevent tumor formation and progression; for another, as a form of proinflammatory death, pyroptosis can provide a favorable microenvironment for tumor cell proliferation, promoting tumor growth [12, 17]. The mechanism of the trigger of pyroptosis is through the activation of the inflammasome, which is a multimolecular complex containing pattern-recognition receptors (PRR) stimulated by an inflammatory response. PRR recognizes certain pathogen-associated molecular patterns (PAMPs) induced by invading pathogens and certain damaged-associated molecular patterns (DAMPs) derived from endogenous pathogens[18].
Many previous studies have shown that AIM2-like receptors (ALRs), Toll-like receptors (TLRs), intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are all associated with pyroptosis [19]. NLRs include eight members (NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NAIP) and AIM2 can activate inflammasomes. Assembly of the inflammasome initiates activation of downstream Caspase 1 is a self-activating proenzyme that converts to a protease and has a physiological role. Caspases-1 activation causes the processing and maturation of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-18, as well as pyroptosis [20].
Pyroptosis has a function in a variety of malignancies. Pyroptosis is also associated with gastric cancer[21], breast cancer[22], Cervical cancer[23]. Given the preceding, growing data suggests that pyroptosis and associated genes have a dual anticancer and tumor-promoting role in tumorigenesis. Assessing the predictive significance of cutaneous melanoma using only a few pyroptosis regular expression patterns is currently insufficient. Therefore, we investigated immune cells directly linked to pyroptosis, as well as a predictive signature based on the impact of the implicated pathways on the TIME. The development of pyroptosis in human disease, as well as its mechanisms, has been extensively researched. Like apoptosis and autophagy, pyroptosis will have a huge influence on cancer detection and therapy. Pyroptosis is increasingly being investigated as an anti-tumor treatment, and our findings show that pyroptosis coupled with immunotherapy to enhance patient prognosis might be a promising therapeutic approach.
Melanoma is one of the malignancies with the highest immunogenicity and has the highest potential to activate immunological responses due to its high genomic mutational load. The TIME is also important for tumor outcome and prognosis. Innate and adaptive immunity act together to prevent melanoma in its early stages and to offer long-term protection against recurrence. The fast and non-specific anti-tumor responses of innate immunity are critical not just for avoiding and reducing melanoma in its early stages, but also for priming strong adaptive immunity in order to provide long-term tumor-specific immune surveillance[24].
In the preliminary stages of tumour development, immune cells ,including Natural killer cells[24], Macrophages[24], neutrophils[25], dendritic cells[26], Th (helper) cells[27], Teff/Tc (effector/cytotoxic) cells, Treg ( regulatory) cells) fulfill their proper function they produce anti-cancer actions via inducing apoptosis in altered cells, generating anti-tumor cytokines, or triggering cytotoxic responses.
By secreting cytokines, activated NK cells help to recruit antigen-presenting cells (APCs), whereas neutrophils, macrophages, and dendritic cells in the tumor niche phagocytose the dead melanoma cells. Subsequently, T cells, including T effector (Teff) cells, cytotoxic T lymphocytes (Tc), and T helper (Th) cells, are activated by APC through the presentation of cancer antigens. Long-term melanoma remission necessitates the activation and growth of these cell types[28]. However,Immune escape is a phenomena caused by the plasticity of melanoma cells, in which cancer cells have a less immunogenic phenotype and the capacity to inhibit anti-tumor immune cells in the tumor microenvironment [29]. Immune escape manifests itself in the tumor microenvironment as a reduction in immune cell infiltration. Immune scores calculated from gene expression data were used to indicate immune features to estimate the infiltration of immune cells in tumor microenvironment[30].
The levels of important infiltrating immune cells and immune related pathways were low in the high-risk group in the TCGA cohort, suggesting a general deterioration of immunological functions, which was confirmed in the GEO cohort. Melanomas of a high-risk group with a low level of immune cell infiltration have a poor prognosis. Immunotherapy will be more effective if there is a higher infiltration of immune cells. We investigated the predictive significance of these PRGs in the preliminary stages and offered a theoretical foundation for further melanoma study.
Cancer is a complicated, diverse disease with a variety of histological characteristics and clinical manifestations. The classification of samples according to pre-determined gene expression characteristics is a well-established method[31]. Depending on the expression of PRGs, we developed a subtyping approach for cutaneous melanoma patients. These regulators were also shown to be linked to a variety of survival hazards. Our analysis eventually resulted in three main points of agreement: (1) The expression of PRGs were entirely different between the two risk score subgroups in cutaneous melanoma patients; (2) The high-risk group was a distinct subgroup with a poor prognosis. (3) The risk score related to pyroptosis was used to represent individuals with various clinical characteristics and was linked to immunotherapy. A high-risk score indicated poor clinical traits as well as a shorter predicted survival time. The risk score has considerable significance for immunotherapy, as evidenced by TIME cell infiltration data. Few studies have focused on the PRGs signature in cutaneous melanoma, and we hoped that our findings would shed light on their roles.
Several limitations should be mentioned in our study. Firstly, we simply registered in the TCGA database to construct the PRG signature, which was then verified by a single GEO database. the accuracy and availability of our biomarker needed to be validated in more datasets, even in prospective research. Moreover, conducting multiple functional studies to elucidate the functions of the 8-PRGs in melanoma was critical. Despite its shortcomings, the predictive usefulness of the PRG signature for OS in melanoma patients cannot be overlooked. Our findings will need to be validated in the future by multi-institutional and well-designed research.
In summary, our research identified a unique genetic signature for predicting the prognosis of cutaneous melanoma patients and lays the groundwork for future research into the connection between and cutaneous melanoma tumor immune microenvironment. our two independent cohorts were used to develop and validate the prognostic predictive signature in cutaneous melanoma patients. The PRG signatures both revealed strong predictors of clinical outcome. Furthermore, the scores obtained from our risk signature based on nine PRGs were independently related for predicting OS in cutaneous melanoma patients. The tumor immune microenvironment differed significantly between PRGs-related risk subgroup. patients with higher risk scores showed an abundance of immune cell infiltration and immune pathways. Finally, the PRG-signature may be a significant predictor of prognosis and may play an essential role in UM patients' tumor immunity.