RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers

Abstract

Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome in high-grade serous ovarian cancer (HGSOC) and other female cancers. Pan-cancer RNA-Seq cluster analysis of immune-related gene expression profiles in The Cancer Genome Atlas (TCGA) from 29 different solid tumors (4446 specimens) identified distinct but concordant gene signatures. Among these immune signatures, Cytotoxic Lymphocyte Immune Signature (CLIS), T-cell trafficking (TCT), and the TCT to M2 tumor-associated macrophage (M2TAM) ratio (TCT:M2TAM) were significantly (p < 0.05) associated with overall survival (OS), using multivariable Cox proportional hazards regression models, in a discovery cohort and two independent validation cohorts of HGSOC patients. Notably, the TCT:M2TAM ratio was highly significant (p ≤ 0.000001) in two HGSOC cohorts. Immune signatures were also significant (p < 0.05) in the presence of tumor cytoreduction, BRCA1/2 mutation, and COL2A1 expression. Importantly, the CLIS and TCT signatures were also validated for prognostic significance (p < 0.05) in TCGA cohorts for endometrial and high tumor mutational burden (Hi-TMB) breast cancer. These immune signatures also have the potential for being predictive in other cancers and for patients following different treatment strategies.Cancers 2020, 12, 620 2 of 12 TME. Studies of the molecular mechanisms involved in immune surveillance within tumors has led to development of promising immunotherapies that have benefited a subset of patients. Furthermore, the immune landscape can also influence response to chemotherapy.High-grade serous ovarian cancer (HGSOC), the most common subtype of epithelial ovarian cancer (EOC), is usually diagnosed at an advanced stage [1]. Although most patients respond to initial adjuvant platinum/taxane-based chemotherapy, the rate of recurrence is relatively high [1,2]. Several clinical, genomic, and immune factors have been correlated with long-term survival, including age, stage, tumor grade, optimal or sub-optimal primary cytoreductive surgery, homologous-recombination deficiency (HRD), BRCA1/BRCA2 mutations, and the presence of intra-tumoral immune cells [3][4][5][6][7][8][9][10]. Patients with high levels of CD8 + tumor infiltrating lymphocytes, as assessed by immunohistochemistry [11][12][13], and patients with high ratios of M1 macrophage cells to M2 tumor-associated macrophage (M2TAM) cells in the TME [14] exhibit improved survival. Further, CXCR3, and its corresponding ligands (CXCL9, CXCL10, and CXCL11), which are frequently expressed by M1 macrophage and other cells in the TME and play a major role in T cell trafficking [15][16][17][18][19][20], are also associated with overall survival (OS) in EOC [21,22].The relationship between immune status determined by gene expression-based biomarkers, treatment re...

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Identification of Tumor Microenvironment-Related Alternative Splicing Events to Predict the Prognosis of Endometrial Cancer

“…And Svetlana et al have found that the higher the tumor-infiltrating CD8+ T cells in EC patients, the higher the overall survival rate would be, which may be a very reliable independent prognostic factor (63). Jones et al have found that cytotoxic lymphocyte immune signature and T-cell trafficking signature were closely related to the prognosis of female malignancies such as EC, further confirming that immune cell infiltration in the tumor microenvironment affected survival and treatment outcomes in patients with EC (64).…”

“…Jones et al. have found that cytotoxic lymphocyte immune signature and T-cell trafficking signature were closely related to the prognosis of female malignancies such as EC, further confirming that immune cell infiltration in the tumor microenvironment affected survival and treatment outcomes in patients with EC ( 64 ).…”