CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers
Background Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8+PD-1+ and CD4+PD-1+ in patients treated...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/2/e004012.full |
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| author | Francois-Xavier Danlos Aurélien Marabelle Roberto Ferrara Benjamin Besse Lydie Cassard Nathalie Chaput Aude Desnoyer Boris Duchemann Marie Naigeon Edouard Auclin Jean-Mehdi Jouniaux Lisa Boselli Jonathan Grivel Laura Mezquita Caroline Caramella |
| author_facet | Francois-Xavier Danlos Aurélien Marabelle Roberto Ferrara Benjamin Besse Lydie Cassard Nathalie Chaput Aude Desnoyer Boris Duchemann Marie Naigeon Edouard Auclin Jean-Mehdi Jouniaux Lisa Boselli Jonathan Grivel Laura Mezquita Caroline Caramella |
| author_sort | Francois-Xavier Danlos |
| collection | DOAJ |
| description | Background Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8+PD-1+ and CD4+PD-1+ in patients treated with immune checkpoint blockers (ICB) is unknown.Methods The CD8+PD-1+ to CD4+PD-1+ ratio (PD-1-Expressing Ratio on Lymphocytes in a Systemic blood sample, or ‘PERLS’) was determined by cytometry in fresh whole blood from patients with aNSCLC before treatment with single-agent ICB targeting PD-1 or programmed cell death-ligand 1 (PD-L1 (discovery cohort). A PERLS cut-off was identified by log-rank maximization. Patients treated with ICB (validation cohort) or polychemotherapy (control cohort) were classified as PERLS+/− (above/below cut-off). Circulating immune cell phenotype and function were correlated with PERLS. A composite score (good, intermediate and poor) was determined using the combination of PERLS and senescent immune phenotype as previously described in aNSCLC.Results In the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS−, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4+ T cells and the increase of memory T cells post-ICB treatment. Accumulation of memory T cells during treatment was linked to CD4+ T cell polyfunctionality. The composite score was evaluated in the pooled cohort (N=68). The median OS for good, intermediate and poor composite scores was NR (95% CI NR to NR), 8.54 months (95% CI 4.96 to NR) and 2.42 months (95% CI 1.97 to 15.5; p=0.001), respectively. The median PFS was 12.60 months (95% CI 9.63 to NR), 2.58 months (95% CI 1.74 to 7.29) and 1.76 months (95% CI 1.31 to 4.57; p<0.0001), respectively.Conclusions Elevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC. |
| format | Article |
| id | doaj-art-0b1156acb9124f3095fba919615b8ea0 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0b1156acb9124f3095fba919615b8ea02024-11-08T14:45:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-02-0110210.1136/jitc-2021-004012CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockersFrancois-Xavier Danlos0Aurélien Marabelle1Roberto Ferrara2Benjamin Besse3Lydie Cassard4Nathalie Chaput5Aude Desnoyer6Boris Duchemann7Marie Naigeon8Edouard Auclin9Jean-Mehdi Jouniaux10Lisa Boselli11Jonathan Grivel12Laura Mezquita13Caroline Caramella14Faculté de médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France2 Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, FranceMedical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Lombardia, Italy5 Comité de Pathologie Thoracique, Gustave Roussy Institute, Villejuif, Île-de-France, FranceImmunomonitoring Laboratory, CNRS3655 & INSERM US23, Université Paris-Saclay, Villejuif, FranceFaculte de Pharmacie, Universite Paris-Saclay, Chatenay-Malabry, Île-de-France, FranceLaboratory for Immunomonitoring in Oncology, Institut Gustave-Roussy, Villejuif, FranceLaboratoire d’Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, Île-de-France, FranceImmunomonitoring Laboratory, CNRS3655 & INSERM US23, Université Paris-Saclay, Villejuif, FranceDepartment of Oncology, Hôpital Européen Georges Pompidou Cancérologie, Paris, FranceImmunomonitoring Laboratory, CNRS3655 & INSERM US23, Université Paris-Saclay, Villejuif, FranceImmunomonitoring Laboratory, CNRS3655 & INSERM US23, Université Paris-Saclay, Villejuif, FranceLaboratoire d’Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, Île-de-France, FranceMedical Oncology Department, Hospital Clinic de Barcelona, Barcelona, SpainDepartment of Radiology, Groupe hospitalier Paris Saint-Joseph, Paris, Île-de-France, FranceBackground Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8+PD-1+ and CD4+PD-1+ in patients treated with immune checkpoint blockers (ICB) is unknown.Methods The CD8+PD-1+ to CD4+PD-1+ ratio (PD-1-Expressing Ratio on Lymphocytes in a Systemic blood sample, or ‘PERLS’) was determined by cytometry in fresh whole blood from patients with aNSCLC before treatment with single-agent ICB targeting PD-1 or programmed cell death-ligand 1 (PD-L1 (discovery cohort). A PERLS cut-off was identified by log-rank maximization. Patients treated with ICB (validation cohort) or polychemotherapy (control cohort) were classified as PERLS+/− (above/below cut-off). Circulating immune cell phenotype and function were correlated with PERLS. A composite score (good, intermediate and poor) was determined using the combination of PERLS and senescent immune phenotype as previously described in aNSCLC.Results In the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS−, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4+ T cells and the increase of memory T cells post-ICB treatment. Accumulation of memory T cells during treatment was linked to CD4+ T cell polyfunctionality. The composite score was evaluated in the pooled cohort (N=68). The median OS for good, intermediate and poor composite scores was NR (95% CI NR to NR), 8.54 months (95% CI 4.96 to NR) and 2.42 months (95% CI 1.97 to 15.5; p=0.001), respectively. The median PFS was 12.60 months (95% CI 9.63 to NR), 2.58 months (95% CI 1.74 to 7.29) and 1.76 months (95% CI 1.31 to 4.57; p<0.0001), respectively.Conclusions Elevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC.https://jitc.bmj.com/content/10/2/e004012.full |
| spellingShingle | Francois-Xavier Danlos Aurélien Marabelle Roberto Ferrara Benjamin Besse Lydie Cassard Nathalie Chaput Aude Desnoyer Boris Duchemann Marie Naigeon Edouard Auclin Jean-Mehdi Jouniaux Lisa Boselli Jonathan Grivel Laura Mezquita Caroline Caramella CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers Journal for ImmunoTherapy of Cancer |
| title | CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers |
| title_full | CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers |
| title_fullStr | CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers |
| title_full_unstemmed | CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers |
| title_short | CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers |
| title_sort | cd8 pd 1 to cd4 pd 1 ratio perls is associated with prognosis of patients with advanced nsclc treated with pd l 1 blockers |
| url | https://jitc.bmj.com/content/10/2/e004012.full |
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