TY - JOUR
T1 - Dual Immune Checkpoint Blockade Induces Analogous Alterations in the Dysfunctional CD8+ T-cell and Activated Treg Compartment
AU - van der Leun, Anne M.
AU - Traets, Joleen J. H.
AU - Vos, Joris L.
AU - Elbers, Joris B. W.
AU - Patiwael, Sanne
AU - Qiao, Xiaohang
AU - Machuca-Ostos, Mercedes
AU - Thommen, Daniela S.
AU - Haanen, John B. A. G.
AU - Schumacher, Ton N. M.
AU - Zuur, Charlotte L.
N1 - Funding Information: We thank Bristol Myers Squibb for scientific input and financial support. This study was funded by the Bristol Myers Squibb International Immuno-Oncology Network and the Riki Foundation, whereas the Netherlands Cancer Institute was the study’s sponsor. Both funding sources had no role in the design and execution of the study, data analysis, or writing of the manuscript. We thank staff of the NKI Flow Cytometry facility and the NKI Genomics Core facility for technical support and input, as well as members of the Zuur and Schumacher laboratories for discussions. Publisher Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response. SIGNIFICANCE: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%–35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance.
AB - To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response. SIGNIFICANCE: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%–35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance.
UR - http://www.scopus.com/inward/record.url?scp=85171991180&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/2159-8290.CD-22-0851
DO - https://doi.org/10.1158/2159-8290.CD-22-0851
M3 - Article
C2 - 37548431
SN - 2159-8274
VL - 13
SP - 2212
EP - 2227
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -