Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy
Open Access
- 6 June 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 11 (7), e10293
- https://doi.org/10.15252/emmm.201910293
Abstract
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.Keywords
Funding Information
- Fundación Científica Asociación Española Contra el Cáncer (PROYE16001ESCO)
- Instituto de Salud Carlos III (PI17/02119)
- Instituto de Salud Carlos III (CP12/03114)
- Fundación Española para la Ciencia y la Tecnología (PRECIPITA)
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