Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy

R. Ferrara; M. Naigeon; E. Auclin; B. Duchemann; L. Cassard; J.M. Jouniaux; L. Boselli; J. Grivel; A. Desnoyer; L. Mezquita; M. Texier; C. Caramella; L. Hendriks; D. Planchard; J. Remon; S. Sangaletti; C. Proto; M.C. Garassino; J.C. Soria; A. Marabelle; A.L. Voisin; S. Farhane; B. Besse; N. Chaput

doi:10.1158/1078-0432.ccr-20-1420

Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy

R. Ferrara, M. Naigeon, E. Auclin, B. Duchemann, L. Cassard, J.M. Jouniaux, L. Boselli, J. Grivel, A. Desnoyer, L. Mezquita, M. Texier, C. Caramella, L. Hendriks, D. Planchard, J. Remon, S. Sangaletti, C. Proto, M.C. Garassino, J.C. Soria, A. MarabelleA.L. Voisin, S. Farhane, B. Besse^*, N. Chaput^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.Experimental Design: The percentage of CD28(-), CD57(+), KLRG1(+) among CD8(+) T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8(+) T cells were assessed in vitro.Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8(+) T cells proliferation, lower IL2 and higher TNF alpha and IFN gamma production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.

Original language	English
Pages (from-to)	492-503
Number of pages	12
Journal	Clinical Cancer Research
Volume	27
Issue number	2
DOIs	https://doi.org/10.1158/1078-0432.ccr-20-1420
Publication status	Published - 15 Jan 2021

Keywords

biomarkers
blockade
docetaxel
elderly-patients
nivolumab
nsclc
outcomes
pd-1
replicative senescence
therapy
NSCLC
DOCETAXEL
REPLICATIVE SENESCENCE
BIOMARKERS
THERAPY
OUTCOMES
NIVOLUMAB
BLOCKADE
ELDERLY-PATIENTS
PD-1

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Cite this

Ferrara, R., Naigeon, M., Auclin, E., Duchemann, B., Cassard, L., Jouniaux, J. M., Boselli, L., Grivel, J., Desnoyer, A., Mezquita, L., Texier, M., Caramella, C., Hendriks, L., Planchard, D., Remon, J., Sangaletti, S., Proto, C., Garassino, M. C., Soria, J. C., ... Chaput, N. (2021). Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy. Clinical Cancer Research, 27(2), 492-503. https://doi.org/10.1158/1078-0432.ccr-20-1420

@article{fa305311296d46d389cd218bd99b2b85,

title = "Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy",

abstract = "Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.Experimental Design: The percentage of CD28(-), CD57(+), KLRG1(+) among CD8(+) T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8(+) T cells were assessed in vitro.Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8(+) T cells proliferation, lower IL2 and higher TNF alpha and IFN gamma production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.",

keywords = "biomarkers, blockade, docetaxel, elderly-patients, nivolumab, nsclc, outcomes, pd-1, replicative senescence, therapy, NSCLC, DOCETAXEL, REPLICATIVE SENESCENCE, BIOMARKERS, THERAPY, OUTCOMES, NIVOLUMAB, BLOCKADE, ELDERLY-PATIENTS, PD-1",

author = "R. Ferrara and M. Naigeon and E. Auclin and B. Duchemann and L. Cassard and J.M. Jouniaux and L. Boselli and J. Grivel and A. Desnoyer and L. Mezquita and M. Texier and C. Caramella and L. Hendriks and D. Planchard and J. Remon and S. Sangaletti and C. Proto and M.C. Garassino and J.C. Soria and A. Marabelle and A.L. Voisin and S. Farhane and B. Besse and N. Chaput",

note = "Funding Information: enrollment in clinical trials), MedImmune (PI, enrollment in clinical trials), and EXELISIS (PI, enrollment in clinical trials) outside the submitted work. J.-C. Soria reports personal fees from AstraZeneca, Abbvie, Bayer, Blend Therapeutics, Boehringer Ingelheim, Cytomix, Daiichi Sankyo, Eli Lilly, Genmab, Guardant Health, Inivata, Merck, Netcancer,Pharmamar, Roche, Servier, andTarveda outsidethesubmittedwork; and was a full-time employee at AstraZeneca from Sep 2017 to Dec 2019. A. Marabelle reports grants from Fondation Malakoff M{\'e}d{\'e}ric and grants and personal fees from Sanofi during the conduct of the study; grants, personal fees, and nonfinancial support from BMS; personal fees and nonfinancial support from MSD; grants from Fondation MSD Avenir; personal fees from Roche/Genentech, Astra Zeneca, Servier, Merck Serono/Pfizer, and GSK outside the submitted work. B. Besse reports grants from Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingel-heim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma,and ToleroPharmaceuticals duringtheconduct ofthe study.N.Chaput reports grants from BMS Fondation during the conduct of the study and grants from SANOFI, GSK, ROCHE, and BMS Fondation, grants and personal fees from Astraze-neca, and grants and other from Cytune Pharma (BSA) outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was supported by a grant from “Fondation Bristol-Myers Squibb pour la recherche en Immunoncologie” and by “SIRIC SOCRATE 2.0 INCa-DGOS-Inserm_12551.” The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: R. Ferrara reports personal fees from MSD (advisory board) outside the submitted work. E. Auclin reports other from Mundipharma (travel expenses) and personal fees from Sanofi Genzymes (lecture) outside the submitted work. B. Duchemann reports personal fees and nonfinancial support from Roche (expert testimony, travel accommodation) and nonfinancial support from Pfizer (travel accommodation) and AstraZeneca (travel accommodation) outside the submitted work. L. Mezquita reports grants, personal fees, and other from Boehringer (research funding), Amgen (research funding), BMS (research funding), Roche Diagnostics (consultant and advisory role), Bristol-Myers Squibb (lectures and educational activities), Tecnofarma (lectures and educational activities), Roche (lectures and educational activities), AstraZeneca (lectures and educational activities), and Chugai (travel, accommodations, expenses), Roche (travel, accommodations, expenses); in addition, L. Mezquita reports mentorship program with key opinion leaders (funded by AstraZeneca) outside the submitted work. C. Caramella reports personal fees from Astra Zeneca, BMS, MSD, and Pfizer outside the submitted work. L.E.L. Hendriks reports grants and other from Roche-Genentech [grants for IIS (institution), fees for adboards (institution), fees for interview sessions (institution), travel reimbursement (self), local PI Roche study], AstraZeneca [grants for IIS (institution), mentorship program with key opinion leaders funded by AstraZeneca, local PI AZ study], and Boehringer Ingelheim [grants for IIS (institution), fees for adboards (institution)]; other from MSD [fees for adboards (institution), speaker (institution)], BMS [fees for adboards (institution), travel reimbursement (self), local PI BMS study]; Eli Lilly [fees for adboards (institution)], and Pfizer [fees for adboards (institution)]; personal fees from Quadia (fees for webinars); other from Novartis (local PI Novartis study), GSK (local PI GSK study), Merck (local PI Merck study), Takeda [fees for adboards (institution), local PI Takeda study], and Blueprint Medicines (local PI Blueprint medicines study) outside the submitted work. D. Planchard reports personal fees from AstraZeneca (consulting, advisory role or lectures), Bristol-Myers Squibb (consulting, advisory role or lectures), Boehringer Ingelheim (consulting, advisory role or lectures), Celgene (consulting, advisory role or lectures), Daiichi Sankyo (consulting, advisory role or lectures), Merck (consulting, advisory role or lectures), Novartis (consulting, advisory role or lectures), Pfizer (consulting, advisory role or lectures), Roche (consulting, advisory role or lectures), Samsung (consulting, advisory role or lectures), prIME Oncology (consulting, advisory role or lectures), and Peer CME (consulting, advisory role or lectures) outside the submitted work; and reports clinical trials research as principal or coinvestigator (institutional financial interests) from AstraZeneca, Bristol-Myers Squibb, Abbvie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo. J. Remon reports nonfinancial support from OSE Immunotherapeutics (travel); personal fees from Boeringher ingelheim (advisory), MSD (advisory), and Pfizer (speaker); personal fees and other from Astrazeneca (advisory), BMS (advisory/ travel), and Roche (advisory/travel) outside the submitted work. C. Proto reports personal fees from BMS and Roche (advisory board) and other from BMS (travel accommodation), MSD (travel accommodation), and Roche (travel accommodation) outside the submitted work. M.C. Garassino reports grants and personal fees from Eli Lilly (PI, MISP in Thimic malignancies; speaker, advisory board), Otsuka Pharma (local PI, enrollment in clinical trials in NSCLC; speaker; advisory board), AstraZe-neca (PI, enrollment and steering committee in clinical trials in NSCLC; consulting, advisory boards, lectures; steering committee), Novartis (PI, enrollment in clinical trials in NSCLC; advisory board), BMS (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Roche (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Pfizer (PI, MISP in Thimic malignancies; advisory board), Celgene (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Incyte (institutional grants; advisory board; speaker), Inivata (advisory board), Bayer (PI, enrollment in clinical trials in mesothelioma; advisory board), MSD (PI, enrollment in clinical trials in NSCLC; consulting, advisory boards, lectures; steering committee), GlaxoSmithKline S.p.A. (local PI, enrollment and steering committee in clinical trials in NSCLC; advisory board), Spectrum Pharmaceuticals (PI, enrollment in clinical trials; advisory board; steering committee), and Blueprint Medicine (PI, enrollment in clinical trials; advisory board; steering committee); personal fees from Takeda (speaker, advisory board; lectures), Boehringer Ingelheim (advisory board), Sanofi-Aventis (advisory board), Daiichi Sankyo (advisory board), and Janssen (advisory board); nonfinancial support from MSD (principal investigator Keynote 189;MISP pembrolizumab in low expressors PD-L1(>50%)), Pfizer (MISP sunitinib in thymic malignancies), and Eli-Lilly (MISP ramucirumab plus carbo-taxol in thymic malignancies); grants from Tiziana Sciences (PI, enrollment in clinical trials Thimic malignancies), Clovis (PI, enrollment in clinical trials in NSCLC), Merck Serono (PI, enrollment in clinical trials in NSCLC), UNITED THERAPEUTICS CORPORATION (institutional grant), Merck KGaA (institutional grant), TURNING POINT (P.I. TRIDENT-1 enrollment in clinical trials), IPSEN (P.I. MM-398-01-03-04 RESILIENT Publisher Copyright: 2020 American Association for Cancer Research.",

year = "2021",

month = jan,

day = "15",

doi = "10.1158/1078-0432.ccr-20-1420",

language = "English",

volume = "27",

pages = "492--503",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "2",

}

Ferrara, R, Naigeon, M, Auclin, E, Duchemann, B, Cassard, L, Jouniaux, JM, Boselli, L, Grivel, J, Desnoyer, A, Mezquita, L, Texier, M, Caramella, C, Hendriks, L, Planchard, D, Remon, J, Sangaletti, S, Proto, C, Garassino, MC, Soria, JC, Marabelle, A, Voisin, AL, Farhane, S, Besse, B & Chaput, N 2021, 'Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy', Clinical Cancer Research, vol. 27, no. 2, pp. 492-503. https://doi.org/10.1158/1078-0432.ccr-20-1420

TY - JOUR

T1 - Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy

AU - Ferrara, R.

AU - Naigeon, M.

AU - Auclin, E.

AU - Duchemann, B.

AU - Cassard, L.

AU - Jouniaux, J.M.

AU - Boselli, L.

AU - Grivel, J.

AU - Desnoyer, A.

AU - Mezquita, L.

AU - Texier, M.

AU - Caramella, C.

AU - Hendriks, L.

AU - Planchard, D.

AU - Remon, J.

AU - Sangaletti, S.

AU - Proto, C.

AU - Garassino, M.C.

AU - Soria, J.C.

AU - Marabelle, A.

AU - Voisin, A.L.

AU - Farhane, S.

AU - Besse, B.

AU - Chaput, N.

N1 - Funding Information: enrollment in clinical trials), MedImmune (PI, enrollment in clinical trials), and EXELISIS (PI, enrollment in clinical trials) outside the submitted work. J.-C. Soria reports personal fees from AstraZeneca, Abbvie, Bayer, Blend Therapeutics, Boehringer Ingelheim, Cytomix, Daiichi Sankyo, Eli Lilly, Genmab, Guardant Health, Inivata, Merck, Netcancer,Pharmamar, Roche, Servier, andTarveda outsidethesubmittedwork; and was a full-time employee at AstraZeneca from Sep 2017 to Dec 2019. A. Marabelle reports grants from Fondation Malakoff Médéric and grants and personal fees from Sanofi during the conduct of the study; grants, personal fees, and nonfinancial support from BMS; personal fees and nonfinancial support from MSD; grants from Fondation MSD Avenir; personal fees from Roche/Genentech, Astra Zeneca, Servier, Merck Serono/Pfizer, and GSK outside the submitted work. B. Besse reports grants from Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingel-heim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma,and ToleroPharmaceuticals duringtheconduct ofthe study.N.Chaput reports grants from BMS Fondation during the conduct of the study and grants from SANOFI, GSK, ROCHE, and BMS Fondation, grants and personal fees from Astraze-neca, and grants and other from Cytune Pharma (BSA) outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was supported by a grant from “Fondation Bristol-Myers Squibb pour la recherche en Immunoncologie” and by “SIRIC SOCRATE 2.0 INCa-DGOS-Inserm_12551.” The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: R. Ferrara reports personal fees from MSD (advisory board) outside the submitted work. E. Auclin reports other from Mundipharma (travel expenses) and personal fees from Sanofi Genzymes (lecture) outside the submitted work. B. Duchemann reports personal fees and nonfinancial support from Roche (expert testimony, travel accommodation) and nonfinancial support from Pfizer (travel accommodation) and AstraZeneca (travel accommodation) outside the submitted work. L. Mezquita reports grants, personal fees, and other from Boehringer (research funding), Amgen (research funding), BMS (research funding), Roche Diagnostics (consultant and advisory role), Bristol-Myers Squibb (lectures and educational activities), Tecnofarma (lectures and educational activities), Roche (lectures and educational activities), AstraZeneca (lectures and educational activities), and Chugai (travel, accommodations, expenses), Roche (travel, accommodations, expenses); in addition, L. Mezquita reports mentorship program with key opinion leaders (funded by AstraZeneca) outside the submitted work. C. Caramella reports personal fees from Astra Zeneca, BMS, MSD, and Pfizer outside the submitted work. L.E.L. Hendriks reports grants and other from Roche-Genentech [grants for IIS (institution), fees for adboards (institution), fees for interview sessions (institution), travel reimbursement (self), local PI Roche study], AstraZeneca [grants for IIS (institution), mentorship program with key opinion leaders funded by AstraZeneca, local PI AZ study], and Boehringer Ingelheim [grants for IIS (institution), fees for adboards (institution)]; other from MSD [fees for adboards (institution), speaker (institution)], BMS [fees for adboards (institution), travel reimbursement (self), local PI BMS study]; Eli Lilly [fees for adboards (institution)], and Pfizer [fees for adboards (institution)]; personal fees from Quadia (fees for webinars); other from Novartis (local PI Novartis study), GSK (local PI GSK study), Merck (local PI Merck study), Takeda [fees for adboards (institution), local PI Takeda study], and Blueprint Medicines (local PI Blueprint medicines study) outside the submitted work. D. Planchard reports personal fees from AstraZeneca (consulting, advisory role or lectures), Bristol-Myers Squibb (consulting, advisory role or lectures), Boehringer Ingelheim (consulting, advisory role or lectures), Celgene (consulting, advisory role or lectures), Daiichi Sankyo (consulting, advisory role or lectures), Merck (consulting, advisory role or lectures), Novartis (consulting, advisory role or lectures), Pfizer (consulting, advisory role or lectures), Roche (consulting, advisory role or lectures), Samsung (consulting, advisory role or lectures), prIME Oncology (consulting, advisory role or lectures), and Peer CME (consulting, advisory role or lectures) outside the submitted work; and reports clinical trials research as principal or coinvestigator (institutional financial interests) from AstraZeneca, Bristol-Myers Squibb, Abbvie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo. J. Remon reports nonfinancial support from OSE Immunotherapeutics (travel); personal fees from Boeringher ingelheim (advisory), MSD (advisory), and Pfizer (speaker); personal fees and other from Astrazeneca (advisory), BMS (advisory/ travel), and Roche (advisory/travel) outside the submitted work. C. Proto reports personal fees from BMS and Roche (advisory board) and other from BMS (travel accommodation), MSD (travel accommodation), and Roche (travel accommodation) outside the submitted work. M.C. Garassino reports grants and personal fees from Eli Lilly (PI, MISP in Thimic malignancies; speaker, advisory board), Otsuka Pharma (local PI, enrollment in clinical trials in NSCLC; speaker; advisory board), AstraZe-neca (PI, enrollment and steering committee in clinical trials in NSCLC; consulting, advisory boards, lectures; steering committee), Novartis (PI, enrollment in clinical trials in NSCLC; advisory board), BMS (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Roche (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Pfizer (PI, MISP in Thimic malignancies; advisory board), Celgene (PI, enrollment in clinical trials in NSCLC; speaker, advisory board), Incyte (institutional grants; advisory board; speaker), Inivata (advisory board), Bayer (PI, enrollment in clinical trials in mesothelioma; advisory board), MSD (PI, enrollment in clinical trials in NSCLC; consulting, advisory boards, lectures; steering committee), GlaxoSmithKline S.p.A. (local PI, enrollment and steering committee in clinical trials in NSCLC; advisory board), Spectrum Pharmaceuticals (PI, enrollment in clinical trials; advisory board; steering committee), and Blueprint Medicine (PI, enrollment in clinical trials; advisory board; steering committee); personal fees from Takeda (speaker, advisory board; lectures), Boehringer Ingelheim (advisory board), Sanofi-Aventis (advisory board), Daiichi Sankyo (advisory board), and Janssen (advisory board); nonfinancial support from MSD (principal investigator Keynote 189;MISP pembrolizumab in low expressors PD-L1(>50%)), Pfizer (MISP sunitinib in thymic malignancies), and Eli-Lilly (MISP ramucirumab plus carbo-taxol in thymic malignancies); grants from Tiziana Sciences (PI, enrollment in clinical trials Thimic malignancies), Clovis (PI, enrollment in clinical trials in NSCLC), Merck Serono (PI, enrollment in clinical trials in NSCLC), UNITED THERAPEUTICS CORPORATION (institutional grant), Merck KGaA (institutional grant), TURNING POINT (P.I. TRIDENT-1 enrollment in clinical trials), IPSEN (P.I. MM-398-01-03-04 RESILIENT Publisher Copyright: 2020 American Association for Cancer Research.

PY - 2021/1/15

Y1 - 2021/1/15

N2 - Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.Experimental Design: The percentage of CD28(-), CD57(+), KLRG1(+) among CD8(+) T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8(+) T cells were assessed in vitro.Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8(+) T cells proliferation, lower IL2 and higher TNF alpha and IFN gamma production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.

AB - Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.Experimental Design: The percentage of CD28(-), CD57(+), KLRG1(+) among CD8(+) T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8(+) T cells were assessed in vitro.Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8(+) T cells proliferation, lower IL2 and higher TNF alpha and IFN gamma production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.

KW - biomarkers

KW - blockade

KW - docetaxel

KW - elderly-patients

KW - nivolumab

KW - nsclc

KW - outcomes

KW - pd-1

KW - replicative senescence

KW - therapy

KW - NSCLC

KW - DOCETAXEL

KW - REPLICATIVE SENESCENCE

KW - BIOMARKERS

KW - THERAPY

KW - OUTCOMES

KW - NIVOLUMAB

KW - BLOCKADE

KW - ELDERLY-PATIENTS

KW - PD-1

U2 - 10.1158/1078-0432.ccr-20-1420

DO - 10.1158/1078-0432.ccr-20-1420

M3 - Article

C2 - 32887723

SN - 1078-0432

VL - 27

SP - 492

EP - 503

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 2

ER -