The Prediction Of Immune Response Characteristics And Treatment Strategies Of Skin Cutaneous Melanoma Based On Characterization Of Inflammatory Response

Objective:The skin cutaneous melanoma is the most aggressive and dangerous form of skin cancer that develops from melanocytes.It is curable in situ at the early stage,but is difficult to treat after metastasis.Melanoma,as one of the most immunogenic tumors,is most likely involved in the response to immunotherapies.Understanding the interactions between melanoma tumor cells and the immune system,as well as the ongoing changes occurring in the tumor microenvironment,is critical to the development of new cancer therapies.Inflammatory responses are involved in regulating the tumor microenvironment,and chronic inflammation promotes tumor development,progression and metastasis,as well as treatment resistance.However,tumor development and malignant progression is also associated with the accumulation of genetic alterations and loss of normal regulatory processes,which leads to the expression of tumor-associated antigens and activates anti-tumor immune responses.Both the activity of inflammatory cells and the type of inflammatory regulators in the tumor microenvironment affect the balance between their pro-tumor and anti-tumor effects.Therefore,this study aims to identify inflammatory prognostic markers and further investigate related immune cells and inflammatory factors in the tumor microenvironment to provide therapeutic strategies.Methods:1.In this study,we used LASSO algorithm to develop a prognosis model.The corresponding IRPscore is calculated.Patients were divided into a high IRPscore group and a low IRPscore group based on the median value to characterize the individual inflammatory response pattern.2.Univariable and multivariable regression analysis was used to confirm the independent prognostic ability of IRPscore,including other clinical parameters.Combined with IRPscore,different clinical parameters were quantified by nomogram to explore the significance of IRPscore in predicting clinical prognosis.3.Compared to the high IRPscore group,the low IRPscore group showed higher tumor mutation load and microsatellite instability,indicating that the low IRPscore group may have higher immunogenicity that further stimulate anti-tumor immune response.Patients in the low IRPscore group had higher expression of antigen presentation molecules,more significant immune pathways and stronger anti-tumor immune responses.4.Multiple drug databases such as Drugbank were integrated to further systematically evaluate the relationship between IRPscore and the predicted efficacy of several treatments,including immunotherapy,radiotherapy,chemotherapy and targeted therapy.Results:1.Kaplan-Meier showed that the survival prognosis of SKCM(skin cutaneous melanoma,SKCM)patients was worse with the increase of IRPscore.2.Univariable and multivariable regression analysis showed that the higher the IRPscore of SKCM patients,the later the clinicopathological parameter T stage and the higher the grade.IRPscore could be used as a risk factor to independently predict the clinical prognosis of patients with SKCM.Compared with other parameters such as age,the graph constructed by combining IRPscore can better predict clinical survival status.In addition,based on the negative correlation between IRPscore and tumor infiltrating immune cells(TIIC),immunomodulators,inflammatory factors and cancer immune cycle,low IRPscore might shape the inflamed tumor microenvironment in SKCM.3.IRPscore was negatively correlated with immune checkpoint and T-cell inflammation score,and positively correlated with TIDE score.Therefore,the low IRPscore group could be more responsive to immunotherapy,while the high IRPscore group was more suitable for radiotherapy and chemotherapy.4.The low IRPscore group showed higher levels of CD8~+T,DC,NK and other immune cell infiltration.The significantly enrichment of antigen presenting molecules and pathways,suggesting a potential anti-tumor immune response.5.IRPscore is negatively correlated with immunomodulators,inflammatory factors and cancer immune cycle.Low IRPscore may shapes an inflammatory tumor microenvironment,suggesting immunologically"hot"tumors in SKCM.6.Immunocheckpoint expression was significantly higher in the low IRPscore group,suggesting that patients in this group may benefit from immune checkpoint blocking therapy.Compared with the high IRPscore group,the low IRPscore group had higher T-cell inflammation score and lower tumor immune dysfunction and rejection,indicating that patients in this group had less immune escape and rejection,and were more sensitive to immunotherapy.7.The high IRPscore group showed high mutation rate of RB1,ERBB2,FANCC and DNA replication pathway,indicating that this group may be more suitable for radiotherapy and chemotherapy.Conclusion:We constructed and validated a novel quantitative prognostic indicator of inflammatory response,IRPscore,which could predict the clinical outcome and the inflammatory profile of TME in SKCM.Meanwhile,the IRPscore can also contribute to predict the clinical response of SKCM patients to several treatment regimens.