Treg-Dominant Tumor Microenvironment Is Responsible for Hyperprogressive Disease after PD-1 Blockade Therapy.
Cancer Immunol Res
; 10(11): 1386-1397, 2022 11 02.
Article
in En
| MEDLINE
| ID: mdl-36169564
ABSTRACT
Programmed cell death 1 (PD-1) blockade therapy can result in dramatic responses in some patients with cancer. However, about 15% of patients receiving PD-1 blockade therapy experience rapid tumor progression, a phenomenon termed "hyperprogressive disease" (HPD). The mechanism(s) underlying HPD has been difficult to uncover because HPD is challenging to reproduce in animal models. Near-infrared photoimmunotherapy (NIR-PIT) is a method by which specific cells in the tumor microenvironment (TME) can be selectively depleted without disturbing other cells in the TME. In this study, we partially depleted CD8+ T cells with NIR-PIT by targeting the CD8ß antigen thereby temporarily changing the balance of T-cell subsets in two different syngeneic tumor models. PD-1 blockade in these models led to rapid tumor progression compared with controls. CD3ε+CD8α+/CD3ε+CD4+FoxP3+ (Teff/Treg) ratios in the PD-1 and NIR-PIT groups were lower than in controls. Moreover, in a bilateral tumor model, low-dose CD8ß-targeted NIR-PIT with anti-PD-1 blockade showed rapid tumor progression only in the tumor exposed to NIR light. In this experiment CD8ß-targeted NIR-PIT in the exposed tumor reduced local CD8+ T cells resulting in a regulatory T-cell (Treg)-dominant TME. In conclusion, this reports an animal model to simulate the Treg-dominant TME, and the data generated using the model suggest that HPD after PD-1 blockade therapy can be attributed, at least in part, to imbalances between effector T cells and Tregs in the TME.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes, Regulatory
/
Neoplasms
Limits:
Animals
Language:
En
Journal:
Cancer Immunol Res
Year:
2022
Document type:
Article