期刊
EMBO MOLECULAR MEDICINE
卷 11, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201910293
关键词
B7-H1; biomarker; immunotherapy; lung cancer; PD-1; PD-L1
资金
- Asociacion Espanola Contra el Cancer (AECC) [PROYE16001ESCO]
- Instituto de Salud Carlos III, Spain, a Precipita Crowdfunding grant (FECYT) [PI17/02119]
- Miguel Servet Fellowship (ISC III, Spain) [CP12/03114]
- Universidad Publica de Navarra
- AECC
- Government of Navarre
The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T-cell proliferative dysfunctionality could be reverted by PD-1/LAG-3 co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.
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