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Pyroptosis-related gene mediated modification patterns and immune cell infiltration landscapes in cutaneous melanoma to aid immunotherapy.

ABSTRACT: Tumor occurrence, infiltration, and metastasis are significantly affected by the tumor microenvironment (TME). Increasing evidence has elucidated TME's clinical significance in prognostic assessment and immunotherapy efficacy. Nonetheless, no studies have reported the potential pyroptosis-related genes (PRGs) function in TME immune cell infiltration. In this study, we systematically analyzed different PRG modification patterns in 685 cutaneous melanoma (CM) cases. We comprehensively explored the relationship between these PRG modification patterns and TME cell infiltration characteristics. Then, we used principal component analysis to construct a pyroptosis scoring system to quantify the PRG modification patterns in each CM patient. Three different PRG modification patterns were identified. Pyroptosis score was confirmed as an independent prognostic factor for CM patients. High pyroptosis score was characterized by high immunophenscore and more lymphocytes infiltration, such as T, B, and NK cells - indicating a strong ability to monitor and clear tumors, which may be responsible for the advantageous survival. Three independent cohorts that received immunotherapy confirmed the significant therapeutic efficacy and clinical benefit in high pyroptosis scores patients. This study revealed that the PRG modification patterns have a crucial effect on the CM complex and diverse microenvironment. Pyroptosis scores might serve as credible predictors of immunotherapy response and prognostic assessment. This provides a new direction for personalized immunotherapy strategies and appropriate immunotherapy candidates screening.

SUBMITTER: Meng J

PROVIDER: S-EPMC8610130 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The "writers" of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification "writers" in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification "writer" scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these "writers" essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.

Project description:Skin cutaneous melanoma (SKCM) constitutes a malignant cutaneous neoplasm characterized by an exceedingly unfavorable prognosis. Over the past years, necroptosis, a manifestation of inflammatory programmed cell demise, has gained substantial traction in its application. However, a conclusive correlation between the expression of necroptosis-related genes (NRGs) and SKCM patient's prognosis remains elusive. In this endeavor, we have undertaken an integrative analysis of genomic data, aiming to provide an exhaustive evaluation of the intricate interplay between melanoma necroptosis and immune-infiltration nuances within the tumor microenvironment. Through meticulous scrutiny, we have endeavored to discern the prognostic potency harbored by individual necroptosis-associated genes. Our efforts culminated in the establishment of a risk stratification framework, allowing for the appraisal of necroptosis irregularities within each afflicted cutaneous melanoma patient. Notably, those SKCM patients classified within the low-risk cohort exhibited a markedly elevated survival quotient, in stark contrast to their high-risk counterparts (p < 0.001). Remarkably, the low-risk cohort not only displayed a more favorable survival rate but also exhibited an enhanced responsiveness to immunotherapeutic interventions, relative to their high-risk counterparts. The outcomes of this investigation proffer insights into a conceivable mechanistic underpinning linking necroptosis-related attributes to the intricacies of the tumor microenvironment. This prompts a conjecture regarding the plausible association between necroptosis characteristics and the broader tumor microenvironmental milieu. However, it is imperative to emphasize that the pursuit of discerning whether the expression profiles of NRG genes can indeed be regarded as viable therapeutic targets necessitates further comprehensive exploration and scrutiny. In conclusion, our study sheds light on the intricate interrelationship between necroptosis-related factors and the tumor microenvironment, potentially opening avenues for therapeutic interventions. However, the prospect of translating these findings into clinical applications mandates rigorous investigation.

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Pyroptosis-related gene mediated modification patterns and immune cell infiltration landscapes in cutaneous melanoma to aid immunotherapy.

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