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Author Notes:

To whom correspondence may be addressed. Email: rahmed@emory.edu or ssramal@ emory.edu.

A.O.K., R.N.P., R.S.A., M.M., F.R.K., T.K.O., R.A., and S.S.R. designed research

A.O.K., R.N.P., S.Y., T.H.N., R.S.A., A.W., H.W., and M.M. performed research

K.Y., L.K., N.T.P., and T.K.O. contributed new reagents/analytic tools

A.O.K., R.N.P., S.Y., T.H.N., R.S.A., G.L.S., M.B., Z.C., C.Z., R.A., and S.S.R. analyzed data

A.O.K., A.W., R.A., and S.S.R. wrote the paper

A.O.K. and R.N.P contributed equally to this work.

R.A. is an inventor on patents held by Emory University that cover the topic of PD-1–directed immunotherapy.

S.S.R. served on the scientific advisory board and received an honorarium from BMS, Merck, Genentech, and Astra Zeneca.


Research Funding:

This work was funded in part by the National Institutes of Health and the T. J. Martell Foundation.


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PD-1
  • cancer immunotherapy
  • T-cell exhaustion
  • CD8 T cells
  • checkpoint inhibition

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

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Journal Title:

Proceedings of the National Academy of Sciences


Volume 114, Number 19


, Pages 4993-4998

Type of Work:

Article | Final Publisher PDF


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-2 Io ), 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.

Copyright information:

© 2017 National Academy of Sciences

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