Dataset Information

Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.

ABSTRACT:

Background

Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown.

Methods

We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using activation-induced marker assays. We determined effector functions representative of T_FH, T_H1, and T_H17/T_H22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status.

Findings

Expression of dysfunction-related molecules, such as transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy associated with infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined functions rather than IC levels: frequencies of cells with T_H1- and T_H17/T_H22-, but not T_FH-related functions, increased. Cells co-expressing T_H1 and T_FH functions showed response to ICB, suggesting that the cell's state rather than function dictates responsiveness to PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation.

Interpretation

Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV infection and other diseases.

Funding

NIH, CIHR, CFI, FRQS.

SUBMITTER: Brunet-Ratnasingham E

PROVIDER: S-EPMC9508408 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.

Brunet-Ratnasingham Elsa E Morou Antigoni A Dubé Mathieu M Niessl Julia J Baxter Amy E AE Tastet Olivier O Brassard Nathalie N Ortega-Delgado Gloria G Charlebois Roxanne R Freeman Gordon J GJ Tremblay Cécile C Routy Jean-Pierre JP Kaufmann Daniel E DE

EBioMedicine 20220920

<h4>Background</h4>Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown.<h4>Methods</h4>We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We ...[more]

PMID: 36150362

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Project description:IntroductionThe magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy.MethodsTo investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC.ResultsAnalysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (≥9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017).ConclusionsInherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer.

Dataset Information

Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.

Background

Methods

Findings

Interpretation

Funding

Publications

Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.

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