Characterization of Immune Infiltration and Construction of a Prediction Model for Overall Survival in Melanoma Patients

Abstract

Reports indicate that the use of anti-programmed cell death-1 (PD-1) and death ligand-1 (PD-L1) monoclonal antibodies for the treatment of patients diagnosed with melanoma has demonstrated promising efficacy. Nonetheless, this therapy is limited by the resistance induced by the tumor microenvironment (TME). As such, understanding the complexity of the TME is vital in enhancing the efficiency of immunotherapy. This study used four different methods to estimate the infiltrating level of immune cells. Besides, we analyzed their infiltration pattern in primary and metastatic melanoma obtained from The Cancer Genome Atlas (TCGA) database. As a consequence, we discovered a significantly higher infiltration of immune cells in metastatic melanoma compared to primary tumor. Consensus clustering identified four clusters in melanoma with different immune infiltration and clusters with higher immune infiltration demonstrated a better overall survival. To elucidate the underlying mechanisms of immune cell infiltration, the four clusters were subdivided into two subtypes denoted as hot and cold tumors based on immune infiltration and predicted immune response. Enrichment analysis of differentially expressed genes (DEGs) revealed different transcriptome alterations in two types of tumors. Additionally, we found tyrosinase-related protein1 (TYRP1) was negatively correlated with CD8A expression. In vitro experiments showed that knockdown TYRP1 promoted the expression of HLA-A, B, and C. Eventually, we constructed a prediction model which was validated in our external cohort. Notably, this model also performed effectively in predicting the survival of patients under immunotherapy. In summary, this work provides a deeper understanding of the state of immune infiltration in melanoma and a prediction model that might guide the clinical treatment of patients with melanoma.

Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics

“…In this study, the UV-low cluster showed a significantly lower leukocyte fraction, proportion of tumor-infiltrating leukocytes, CYT score, and TCR richness than the UV-high cluster. It has been established that low immune cell infiltration is associated with poor clinical outcome ( Barnes and Amir, 2017 ; Thorsson et al, 2018 ; Li et al, 2021 ). Therefore, the poorer survival in the UV-low cluster may be explained by lower activation of antitumor immunity.…”

TimiGP: inferring inter-cell functional interactions and clinical values in the tumor immune microenvironment through gene pairs

“…Due to inter-cell crosstalk, different immune cells are often closely regulated and hence co-infiltrate the tumor microenvironment 29 . To demonstrate this, we applied eight transcriptome-based cell-type quantification methods [15][16][17][18][19][20][21][22][23][24][25] to metastatic melanoma, which is known to be a highly immune infiltrated cancer type (immune "hot") 30,31 . As expected, estimated cell abundances were strongly positively correlated to each other (Figure S1A).…”

B7H6 silencing increases chemosensitivity to dacarbazine and suppresses cell survival and migration in cutaneous melanoma

“…Melanoma is divided into cutaneous and noncutaneous tumors based on the location of the primary tumor [4]. Cutaneous melanoma, an invasive cancer with high metastatic potential, occurs from cells in the skin and mucous membranes called melanocytes, which are responsible for pigmentation in the skin [3,5,6]; however, it accounts for a small percentage (<5%) of all cancers [7]. Although the 5-year survival rate for melanoma patients is below 5, the chance of survival is less than 1% when metastasis occurs [7].…”