Sex differences in expression of immune elements emerge in children, young adults and mice with osteosarcoma

Abstract

Background Males < 40 years old are more likely to be diagnosed with and die from osteosarcoma (OS). The underlying mechanisms may depend on sex differences in immune response. Methods We used SEER data to estimate survival differences between males and females aged < 40 years at OS diagnosis. In NCI TARGET-OS cases, we determined sex differences in gene expression, conducted Gene Set Enrichment Analysis (GSEA), and applied the LM22 signature to identify biologic sex differences. We compared sex differences in gene expression profiles in TARGET-OS to those observed in Sleeping Beauty (SB) transposon mutagenesis accelerated Trp53R270H-mutant mouse-OS and healthy adult osteoblasts. Results Males had worse 17-year overall survival than females (SEER p < 0.0001). From 87 TARGET-OS cases, we observed 1018 genes and 69 pathways that differed significantly by sex (adjusted p < 0.05). Pathway and gene lists overlapped with those from mice (p = 0.03) and healthy osteoblasts (p = 0.017), respectively. Pathways that differed significantly by sex were largely immune-based and included the PD-1/PD-L1 immunotherapy pathway. We observed sex differences in M2 macrophages (LM22; p = 0.056) and M1-M2 macrophage transition (GSEA; p = 0.037) in TARGET-OS. LM22 trends were similar in mice. Twenty-four genes differentially expressed by sex in TARGET-OS had existing cancer therapies. Conclusions Sex differences in OS gene expression were similar across species and centered on immune pathways. Identified sex-specific therapeutic targets may improve outcomes in young individuals with OS.

Comprehensive Analysis of Tumor Immune Microenvironment Characteristics for the Prognostic Prediction and Immunotherapy of Oral Squamous Cell Carcinoma

“…CIBERSORT is a deconvolution method applied for the characterization of cell composition of a complex tissue (Peng et al, 2021). LM22 is a leukocyte gene signature matrix that contains the expression levels of 547 genes for distinguishing 22 human hematopoietic cell phenotypes (Mills et al, 2021). In this study, CIBERSORT combined with LM22 signature matrix were used to quantify the infiltration levels of twenty-two immune cells in OSCC.…”

RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases

“…This increased prevalence of OS among males has been consistently reported for several different races as well [12]. Furthermore, many studies found male OS patients to have worse 5-year [12][13][14][15][16] or event-free [17] survival compared to females. In fact, males with OS have a higher incidence of distant disease and metastases compared to female patients [13] and may be less sensitive to chemotherapy as seen in similar cancers [18].…”

“…Furthermore, many studies found male OS patients to have worse 5-year [12][13][14][15][16] or event-free [17] survival compared to females. In fact, males with OS have a higher incidence of distant disease and metastases compared to female patients [13] and may be less sensitive to chemotherapy as seen in similar cancers [18]. OS also tends to affect patients during periods of rapid growth.…”

Investigating and Practicing Orthopedics at the Intersection of Sex and Gender: Understanding the Physiological Basis, Pathology, and Treatment Response of Orthopedic Conditions by Adopting a Gender Lens: A Narrative Overview

“…Osteosarcoma, a bone tumor displaying a bimodal peak in incidence during the teen and late adult years [72], and soft tissue malignancies were found to be more common in male populations than in females across every race/ethnicity group, with an overall ratio of males to females computed at 1.3:1. Specifically, the incidence rate for males was 8.1 (with a 95% confidence interval of 7.7-8.6) compared to an incidence rate of 6.2 for females (with a 95% confidence interval of 5.8-6.6) [73].…”