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

Jinzhi Meng,Jun Yao,Xing Huang,Xifan Zheng,Yue Qiu,Junpu Huang,Zhenpei Wen

doi:10.18632/aging.203687

Jinzhi Meng, Jun Yao + Show 5 more

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https://doi.org/10.18632/aging.203687

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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.

Highlights

Cutaneous melanoma (CM) is the most aggressive skin cancer and accounts for 1.7% of the global malignancies incidence
Further analyzing pyroptosis-related gene (PRG) prognostic role, we found that TNF and AIM2 were significantly associated with the CM patients’ overall prognosis
Our results showed that the alterations of copy number variation (CNV) could be the prominent factors resulting in perturbations on the PRG regulators expression. (Figure 1F)

Summary

Introduction

Cutaneous melanoma (CM) is the most aggressive skin cancer and accounts for 1.7% of the global malignancies incidence (approximately 232,100 cases). Approximately 55,500 people die from malignant melanoma each year, accounting for 0.7% of cancer deaths [1, 2]. Immunotherapy can restore immune surveillance and kill cancer cells by the host’s natural immune system activation and tumor’s immune escape mechanism break [1, 4,5,6]. It has become a breakthrough strategy in cancer treatment options, especially with the advent of anti-PD-1/PD-L1 targeting drugs, which are important to improve some CM patients’ overall survival. There is an urgent need for a reliable marker to identify suitable immunotherapy candidates to provide precise treatment

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