Sex-associated molecular differences for cancer immunotherapy

Ye, Youqiong; Jing, Ying; Li, Liang; Mills, Gordon B.; Diao, Lixia; Li, Hong; Han, Leng

doi:10.1038/s41467-020-15679-x

Cited by 177 publications

(149 citation statements)

References 44 publications

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“…However, ICB is effective in only 10-40% of patients for reasons that remain unclear. Meta-analyses of clinical trials in multiple cancer types treated with ICB suggest that young and female patients are characterized by low response rates [4][5][6][7][8] . The reason(s) for the poor response of these two populations remains elusive.…”

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confidence: 99%

Strength of immune selection in tumors varies with sex and age

et al. 2020

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Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHCbased immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.

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confidence: 99%

Strength of immune selection in tumors varies with sex and age

et al. 2020

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“…Of note, sex-based immunological differences in lung adenocarcinoma might have an impact on immunotherapy response. Different studies have addressed the role of sex in immunotherapy [40,[51][52][53] , establishing improved survival for female NSCLC patients. The discovered molecular pathways differentially activated between male and female lung adenocarcinoma patients may underlie phenotypic differences regarding immunotherapy response.…”

Section: Discussionmentioning

confidence: 99%

Functional signatures in non-small-cell lung cancer: a systematic review and meta-analysis of sex-based differences in transcriptomic studies

Pérez-Díez

Hidalgo

Malmierca-Merlo

et al. 2020

Preprint

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While studies have established the existence of differences in the epidemiological and clinical patterns of lung adenocarcinoma between male and female patients, we know relatively little regarding the molecular mechanisms underlying such sex-based differences. In this study, we explore said differences through a meta-analysis of transcriptomic data. We performed a meta-analysis of the functional profiling of nine public datasets that included 1,366 samples from Gene Expression Omnibus and The Cancer Genome Atlas databases. Meta-analysis results show an enrichment of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways related to the immune response, nucleic acid metabolism, and purinergic signaling. We discovered the overrepresentation of terms associated with the immune response, particularly with acute inflammatory response, and purinergic signaling in female lung adenocarcinoma patients, which could influence reported clinical differences. Further evaluations of the identified differential biological processes and pathways could lead to the discovery of new biomarkers and therapeutic targets. Our findings also emphasize the relevance of sex-specific analyses in biomedicine, which represents a crucial aspect influencing biological variability in disease.

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“…The differences associated with gender have been previously assessed in pan-cancer studies, most of them using TCGA cancer datasets, resulting in divergent patterns for sex bias in gene expression or immune features across multiple cancer types have been revealed [40,52]. Nevertheless, the functional consequences at the level of cell behavior or fate of gender bias in gene expression have remained mainly unknown.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

Çubuk

Can

Peña‐Chilet

et al. 2020

Cells

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Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.

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Sex-associated molecular differences for cancer immunotherapy

Cited by 177 publications

References 44 publications

Strength of immune selection in tumors varies with sex and age

Strength of immune selection in tumors varies with sex and age

Functional signatures in non-small-cell lung cancer: a systematic review and meta-analysis of sex-based differences in transcriptomic studies

Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

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