TY - JOUR
T1 - Comprehensive immunophenotyping reveals distinct tumor microenvironment alterations in anti-PD-1 sensitive and resistant syngeneic mouse model
AU - Inoue, Hiroyuki
AU - Hamasaki, Takayuki
AU - Inoue, Kazuhiko
AU - Nakao, Akira
AU - Ebi, Noriyuki
AU - Minomo, Hirofumi
AU - Nagata, Ichiro
AU - Fujita, Masaki
AU - Horai, Naoto
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - The advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway has revolutionized cancer treatment, resulting in improved clinical outcomes. However, resistance remains a critical challenge. This study aimed to comparatively elucidate immunophenotypic changes in syngeneic mouse models sensitive (MC-38) or resistant (LLC1) to anti-PD-1 monoclonal antibody (mAb) treatment. In the sensitive MC-38 model, anti-PD-1 therapy increased dendritic cells (DCs) and macrophages, while decreasing myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. Enhanced expression of antigen presentation molecules (MHC I/II) and costimulatory molecules (CD80/CD86) was observed on tumor-associated DCs and macrophages. Tumor-infiltrating CD4+T, CD8+T, regulatory T, NK, and NKT cells also significantly increased. Importantly, treatment boosted lymphocyte cytotoxic potential, with perforin identified as a key marker of efficacy. Notably, perforin expression in CD4+T and NKT cells strongly negatively correlated with tumor volume. In contrast, the resistant LLC1 model exhibited minimal immunophenotypic changes upon treatment. These findings highlight critical immune modifications induced by anti-PD-1 therapy, particularly the role of perforin, and the DC/MDSC ratio in predicting therapeutic outcomes. This research offers valuable insights into potential predictive biomarkers and informs strategies to overcome resistance, emphasizing the complex interplay between anti-PD-1 treatment and the tumor microenvironment, ultimately aiming to improve immunotherapy response rates.
AB - The advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway has revolutionized cancer treatment, resulting in improved clinical outcomes. However, resistance remains a critical challenge. This study aimed to comparatively elucidate immunophenotypic changes in syngeneic mouse models sensitive (MC-38) or resistant (LLC1) to anti-PD-1 monoclonal antibody (mAb) treatment. In the sensitive MC-38 model, anti-PD-1 therapy increased dendritic cells (DCs) and macrophages, while decreasing myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. Enhanced expression of antigen presentation molecules (MHC I/II) and costimulatory molecules (CD80/CD86) was observed on tumor-associated DCs and macrophages. Tumor-infiltrating CD4+T, CD8+T, regulatory T, NK, and NKT cells also significantly increased. Importantly, treatment boosted lymphocyte cytotoxic potential, with perforin identified as a key marker of efficacy. Notably, perforin expression in CD4+T and NKT cells strongly negatively correlated with tumor volume. In contrast, the resistant LLC1 model exhibited minimal immunophenotypic changes upon treatment. These findings highlight critical immune modifications induced by anti-PD-1 therapy, particularly the role of perforin, and the DC/MDSC ratio in predicting therapeutic outcomes. This research offers valuable insights into potential predictive biomarkers and informs strategies to overcome resistance, emphasizing the complex interplay between anti-PD-1 treatment and the tumor microenvironment, ultimately aiming to improve immunotherapy response rates.
KW - Anti-PD-1 antibody
KW - Cytolytic activation marker
KW - Syngeneic mouse models
KW - Tumor immunophenotyping
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UR - http://www.scopus.com/inward/citedby.url?scp=105000074908&partnerID=8YFLogxK
U2 - 10.1038/s41598-025-91979-w
DO - 10.1038/s41598-025-91979-w
M3 - Article
C2 - 40064915
AN - SCOPUS:105000074908
SN - 2045-2322
VL - 15
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 8311
ER -