Contribution of systemic T cell immunity to clinical efficacy of anti-PD-L1/PD-1 immunotherapies in lung cancer

Resumen

A high percentage of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that the proportion of highly differentiated (THD) CD4 T cell population can identify potential responders to PD-L1/PD-1 blockade therapy as quantified from peripheral blood samples before treatment initiation. Indeed, a baseline high proportion of CD4 THD (>40%) is an indicator of functional systemic CD4 immunity which turned to be a differential factor for clinical responses. In these patients, CD4 T cells possessed significant proliferative capacities and low co‐expression of PD‐1/LAG‐3 following activation, and were responsive to PD‐1 blockade ex vivo and in vivo. In addition, quantification of highly differentiated CD4 T cells in combination with PD‐L1 tumor positivity identified a group of patients with response rates to immunotherapy of about 70%. In contrast, patients with low percentages of CD4 THD (<40%) did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients exhibited proliferative dysfunctionality, strongly co‐upregulated PD‐1/LAG‐3 and were largely refractory to PD‐1 monoblockade. Systemic CD8 immunity only recovered by PD-L1/PD-1 blockade therapy in patients who had baseline functional CD4 immunity. In contrast, baseline systemic T cell proliferative dysfunctionality in patients refractory to PD-1/PD-L1 monoblockade strategies could be reverted by PD‐1/LAG‐3 co‐blockade confirming that PD-1/LAG-3 co-expression was a contributor to T cell dysfunctionality. These results provide a strong rationale for the combination of PD-L1/PD-1 and LAG-3 blockade therapies in patients exhibiting baseline CD4 T cell dysfunctionality.