Ferrara Roberto, Naigeon Marie, Auclin Edouard, Duchemann Boris, Cassard Lydie, Jouniaux Jean-Mehdi, Boselli Lisa, Grivel Jonathan, Desnoyer Aude, Mezquita Laura, Texier Matthieu, Caramella Caroline, Hendriks Lizza, Planchard David, Remon Jordi, Sangaletti Sabina, Proto Claudia, Garassino Marina C, Soria Jean-Charles, Marabelle Aurelien, Voisin Anne-Laure, Farhane Siham, Besse Benjamin, Chaput Nathalie
Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and INSERM-US23, Villejuif, France.
Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
Clin Cancer Res. 2021 Jan 15;27(2):492-503. doi: 10.1158/1078-0432.CCR-20-1420. Epub 2020 Sep 4.
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.
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 cut-off 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 the ICI discovery cohort ( = 37), SIP cut-off was 39.5%, 27% of patients were SIP. In the ICI validation cohort ( = 46), SIP status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, = 0.02]. SIP status was significantly associated with circulating specific immunephenotypes, lower CD8 T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( = 83), SIP status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( = 61), 11% of patients were SIP. SIP status did not correlate with outcomes upon PCT.
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..
CD28、CD57和KLRG1先前已被确定为T细胞免疫衰老的标志物。免疫衰老对晚期非小细胞肺癌（aNSCLC）患者接受抗PD（L）-1（免疫检查点抑制剂，ICI）或铂类化疗（PCT）的影响尚不清楚。
通过流式细胞术评估aNSCLC患者在接受单药ICI治疗前（发现队列）血液中CD8 T细胞中CD28、CD57、KLRG1的百分比[衰老免疫表型（SIP）]。通过对数秩最大化方法确定SIP临界值，并据此对接受ICI治疗（验证队列）或PCT的aNSCLC患者进行分类。评估SIP CD8 T细胞的增殖和功能特性。
在ICI发现队列（n = 37）中，SIP临界值为39.5%，27%的患者为SIP。在ICI验证队列（n = 46）中，28%的患者存在SIP状态，且与较差的客观缓解率（ORR；0%对30%，P = 0.04）、中位无进展生存期（PFS）[1.8（95%置信区间（CI），1.3 - NR）对6.4（95% CI，2 - 19）个月，P = 0.009]和中位总生存期（OS）[2.8（95% CI，2.0 - NR）对20.8（95% CI，6.0 - NR）个月，P = 0.02]显著相关。SIP状态与循环特异性免疫表型、较低的CD8 T细胞增殖、较低的IL2以及较高的TNFα和IFNγ产生显著相关。在ICI汇总人群（n = 83）中，SIP状态与任何临床特征均无相关性，但与显著更差的ORR、PFS和OS相关。在PCT队列（n = 61）中，1
