Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-05, Vol.114 (19), p.4993-4998
• Main Authors: Kamphorst, Alice O., Pillai, Rathi N., Yang, Shu, Nasti, Tahseen H., Akondy, Rama S., Wieland, Andreas, Sica, Gabriel L., Yu, Ke, Koenig, Lydia, Patel, Nikita T., Behera, Madhusmita, Wu, Hong, McCausland, Megan, Chen, Zhengjia, Zhang, Chao, Khuri, Fadlo R., Owonikoko, Taofeek K., Ahmed, Rafi, Ramalingam, Suresh S.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized - administration & dosage; Apoptosis; Bcl protein; Bcl-2 protein; Biological Sciences; Biomarkers; Blood; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; CD27 antigen; CD28 antigen; CD38 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell activation; Cell death; Cell proliferation; Cell Proliferation - drug effects; CTLA-4 protein; Effector cells; Female; Histocompatibility antigen HLA; Humans; Immunology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Male; Molecules; Non-small cell lung carcinoma; Patients; PD-1 protein; Peripheral blood; Programmed Cell Death 1 Receptor - antagonists & inhibitors; T cell receptors; Therapy; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1705327114

Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients’ responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non–small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1–targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR⁺, CD38⁺, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses to PD-1–targeted therapies.