PT  - JOURNAL ARTICLE
AU  - Andre Kunert
AU  - Edwin A. Basak
AU  - Daan P. Hurkmans
AU  - Hayri E. Balcioglu
AU  - Yarne Klaver
AU  - Mandy van Brakel
AU  - Astrid A. M. Oostvogels
AU  - Cor H. J. Lamers
AU  - Sander Bins
AU  - Stijn L. W. Koolen
AU  - Astrid A. M. van der Veldt
AU  - Stefan Sleijfer
AU  - Ron H. J. Mathijssen
AU  - Joachim G. J. V. Aerts
AU  - Reno Debets
TI  - CD45RA<sup>+</sup>CCR7<sup>−</sup> CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab
AID  - 10.1186/s40425-019-0608-y
DP  - 2019 Dec 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - 149
VI  - 7
IP  - 1
4099  - http://jitc.bmj.com/content/7/1/149.short
4100  - http://jitc.bmj.com/content/7/1/149.full
SO  - J Immunother Cancer2019 Dec 01; 7
AB  - Background Checkpoint inhibitors have become standard care of treatment for non-small cell lung cancer (NSCLC), yet only a limited fraction of patients experiences durable clinical benefit, highlighting the need for markers to stratify patient populations.Methods To prospectively identify patients showing response to therapy, we have stained peripheral blood samples of NSCLC patients treated with 2nd line nivolumab (n = 71), as well as healthy controls, with multiplex flow cytometry. By doing so, we enumerated 18 immune cell subsets and assessed expression for 28 T cell markers, which was followed by dimensionality reduction as well as rationale-based analyses.Results In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.Conclusions This study demonstrates that high numbers of peripheral CD8 T cells expressing differentiation markers and lacking co-stimulatory receptors at baseline are associated with response to nivolumab in NSCLC patients.Andre Kunert and Edwin A. Basak contributed equally as first authorsJoachim G.J.V. Aerts and Reno Debets contributed equally as senior authorsAbbreviations:BORBest overall responseBTLAB- and T-lymphocyte attenuatorCDCluster of differentiationCTLA-4Cytotoxic T-lymphocyte–associated antigen 4dMMRmismatch repair deficiencyFMOFluorescence minus oneICOSInducible T cell co-stimulatorLAG3Lymphocyte-activation gene 3MSIMicrosatellite instabilityNSCLCNon-small cell lung cancerPDProgressive diseasePD-1Programmed death 1 receptorPD-L1Programmed-death ligand 1PRPartial responseSDStable diseaseTCRT cell receptorTIM3T cell immunoglobulin and mucin-domain containing-3TMBTumor mutational burden TMBtSNEt-distributed stochastic neighbor embedding