Wakiyama et al. conjugated IR700 with anti-CD8β to generate anti-CD8β–IR700, a near-infrared photoimmunotherapy (NIR-PIT) that selectively depletes CD8+ cells upon NIR light exposure. Combination of anti-PD-1 therapy with NIR-PIT systemically decreased CD8+ T cells, led to an increase in CD3ε+CD4+Foxp3+ Tregs, and induced more rapid tumor progression than no therapy or NIR-PIT alone in syngeneic tumor models. In a bilateral tumor model, CD8β-targeted NIR-PIT combined with anti-PD-1 induced rapid tumor progression in the NIR-light irradiated side only, with the depletion of local CD8+ T cells resulting in a Treg-dominant TME.
Contributed by Shishir Pant
ABSTRACT: Programmed cell death 1 (PD-1) blockade therapy can result in dramatic responses in some cancer patients. 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 CD8_ 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 to controls. CD3_+CD8_+/CD3_+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 CD8_-targeted NIR-PIT with anti-PD-1 blockade showed rapid tumor progression only in the tumor exposed to NIR light. In this experiment CD8_-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.
Author Info: (1) National Cancer Institute, Bethesda, MD, United States. (2) National Cancer Institute, Bethesda, MD, United States. (3) National Cancer Institute, Bethesda, MD, United States.
Author Info: (1) National Cancer Institute, Bethesda, MD, United States. (2) National Cancer Institute, Bethesda, MD, United States. (3) National Cancer Institute, Bethesda, MD, United States. (4) National Cancer Institute, Bethesda, MD, United States. (5) National Cancer Institute, Bethesda, MD, United States. (6) National Cancer Institute, Bethesda, MD, United States. (7) National Cancer Institute, Bethesda, MD, United States. (8) National Cancer Institute, Bethesda, MD, United States. (9) National Cancer Institute, Bethesda, MD, United States. (10) National Cancer Institute, Bethesda, MD, United States.
