TY - JOUR
T1 - Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer
AU - Granier, Clemence
AU - De Guillebon, Eleonore
AU - Blanc, Charlotte
AU - Roussel, Helene
AU - Badoual, Cecile
AU - Colin, Elia
AU - Saldmann, Antonin
AU - Gey, Alain
AU - Oudard, Stephane
AU - Tartour, Eric
N1 - Publisher Copyright:
© European Society for Medical Oncology (unless otherwise stated in the text of the article) 2017. All rights reserved.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation. These antibodies have multiple mechanisms of action. At the cellular level, these antibodies restore the activation signalling pathway and reprogram T cell metabolism. Tumour cells become resistant to apoptosis when an intracellular PD-L1 signalling is blocked. CD8 + T cells are considered to be the main effectors of the blockade of inhibitory receptors. Certain CD8 + T cell subsets, such as non-hyperexhausted (CD28 +, T-bet high, PD-1 int), follicular-like (CXCR-5 +) or resident memory CD8 + T cells, are more prone to be reactivated by anti-PD-1/PD-L1 monoclonal antibody (mAb). In the future, the challenge will be to rationally combine drugs able to make the tumour microenvironment more permissive to immunotherapy in order to potentiate its clinical activity.
AB - The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation. These antibodies have multiple mechanisms of action. At the cellular level, these antibodies restore the activation signalling pathway and reprogram T cell metabolism. Tumour cells become resistant to apoptosis when an intracellular PD-L1 signalling is blocked. CD8 + T cells are considered to be the main effectors of the blockade of inhibitory receptors. Certain CD8 + T cell subsets, such as non-hyperexhausted (CD28 +, T-bet high, PD-1 int), follicular-like (CXCR-5 +) or resident memory CD8 + T cells, are more prone to be reactivated by anti-PD-1/PD-L1 monoclonal antibody (mAb). In the future, the challenge will be to rationally combine drugs able to make the tumour microenvironment more permissive to immunotherapy in order to potentiate its clinical activity.
KW - CD8 + T cells
KW - checkpoint inhibitors
KW - exhaustion
KW - immunotherapy
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85031736840&partnerID=8YFLogxK
U2 - 10.1136/esmoopen-2017-000213
DO - 10.1136/esmoopen-2017-000213
M3 - Review article
AN - SCOPUS:85031736840
SN - 2059-7029
VL - 2
JO - ESMO Open
JF - ESMO Open
IS - 2
M1 - e000213
ER -