TY - JOUR
T1 - CD45RA+CCR7- CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab
AU - Kunert, Andre
AU - Basak, Edwin A.
AU - Hurkmans, Daan P.
AU - Balcioglu, Hayri E.
AU - Klaver, Yarne
AU - Van Brakel, Mandy
AU - Oostvogels, Astrid A.M.
AU - Lamers, Cor H.J.
AU - Bins, Sander
AU - Koolen, Stijn L.W.
AU - Van Der Veldt, Astrid A.M.
AU - Sleijfer, Stefan
AU - Mathijssen, Ron H.J.
AU - Aerts, Joachim G.J.V.
AU - Debets, Reno
N1 - Funding:
This research was entirely funded by the Departments of Medical Oncology
and Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/6/8
Y1 - 2019/6/8
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85067039791&partnerID=8YFLogxK
U2 - 10.1186/s40425-019-0608-y
DO - 10.1186/s40425-019-0608-y
M3 - Article
C2 - 31176366
SN - 2051-1426
VL - 7
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 1
M1 - 149
ER -