Senescent CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer

The majority of lung cancer patients are intrinsically refractory to PD-L1/PD-1 blockade monotherapy. There is recent evidence indicating that this therapy can have serious deleterious effects by accelerating disease progression and death in a group of patients called hyperprogressors. Hence, identification of patients as hyperprogressors, non-responders and potential responders prior to therapy is of critical importance in clinical oncology. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy heavily relies on baseline circulating senescent CD4 T cells (Tsens). Non-small cell lung cancer (NSCLC) patients segregate in two non-overlapping groups; patients with high or with low numbers of baseline circulating Tsens. Low Tsen numbers prior to therapy unequivocally identify intrinsic non-responders, which include hyperprogressors. Additionally, unique dynamic changes in Tsens following the first cycle of therapy discriminate responders from progressors. Patients with hyperprogressive disease undergo an aberrant immunological phenomenon consisting on potent systemic proliferation of Tsens right after the first cycle of therapy (Tsen burst). ROC analysis was used to test the robustness of Tsen quantification as a predictive biomarker for primary resistance. A cut-off value of