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.