Functional systemic CD4 immunity is required for clinical responses to PD‐L1/PD‐1 blockade therapy

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.