PMID- 38271187
OWN - NLM
STAT- MEDLINE
DCOM- 20240129
LR  - 20240206
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 65
IP  - 1
DP  - 2024 Jan 2
TI  - Tumor Pigmentation Does Not Affect Light-Activated Belzupacap Sarotalocan 
      Treatment but Influences Macrophage Polarization in a Murine Melanoma Model.
PG  - 42
LID - 10.1167/iovs.65.1.42 [doi]
LID - 42
AB  - PURPOSE: Pigmentation in uveal melanoma is associated with increased malignancy 
      and is known as a barrier for photodynamic therapy. We investigated the role of 
      pigmentation in tumor behavior and the response to light-activated Belzupacap 
      sarotalocan (Bel-sar) treatment in a pigmented (wild type) and nonpigmented 
      (tyrosinase knock-out [TYR knock-out]) cell line in vitro and in a murine model. 
      METHODS: The B16F10 (TYR knock-out) was developed using CRISPR/Cas9. After the 
      treatment with light-activated Bel-sar, cytotoxicity and exposure of 
      damage-associated molecular patterns (DAMPs) were measured by flow cytometry. 
      Treated tumor cells were co-cultured with bone marrow-derived macrophages (BMDMs) 
      and dendritic cells (DCs) to assess phagocytosis and activation. Both cell lines 
      were injected subcutaneously in syngeneic C57BL/6 mice. RESULTS: Knock-out of the 
      tyrosinase gene in B16F10 led to loss of pigmentation and immature melanosomes. 
      Pigmented tumors contained more M1 and fewer M2 macrophages compared with 
      amelanotic tumors. Bel-sar treatment induced near complete cell death, 
      accompanied with enhanced exposure of DAMPs in both cell lines, resulting in 
      enhanced phagocytosis of BMDMs and maturation of DCs. Bel-sar treatment induced a 
      shift to M1 macrophages and delayed tumor growth in both in vivo tumor models. 
      Following treatment, especially the pigmented tumors and their draining lymph 
      nodes contained IFN-gamma positive CD8+T cells. CONCLUSIONS: Pigmentation 
      influenced the type of infiltrating macrophages in the tumor, with more M1 
      macrophages in pigmented tumors. Belzupacap sarotalocan treatment induced 
      immunogenic cell death and tumor growth delay in pigmented as well as in 
      nonpigmented models and stimulated M1 macrophage influx in both models.
FAU - Ma, Sen
AU  - Ma S
AD  - Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - Huis In't Veld, Ruben V
AU  - Huis In't Veld RV
AD  - Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
AD  - Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
AD  - Department of Immunology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - Hao, Yang
AU  - Hao Y
AD  - Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
AD  - Department of Laboratory Animals, College of Animal Sciences, Jilin University, 
      Changchun, China.
FAU - Gu, Zili
AU  - Gu Z
AD  - Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - Rich, Cadmus
AU  - Rich C
AD  - Aura Biosciences, Inc., Boston, Massachusetts, United States.
FAU - Gelmi, Maria Chiara
AU  - Gelmi MC
AD  - Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - Mulder, Aat A
AU  - Mulder AA
AD  - Department of Electron Microscopy, Leiden University Medical Center (LUMC), 
      Leiden, The Netherlands.
FAU - van Veelen, Peter A
AU  - van Veelen PA
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), 
      Leiden, The Netherlands.
FAU - Vu, T Khanh H
AU  - Vu TKH
AD  - Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - van Hall, Thorbald
AU  - van Hall T
AD  - Department of Medical Oncology, Oncology Institute, Leiden University Medical 
      Center (LUMC), Leiden, The Netherlands.
FAU - Ossendorp, Ferry A
AU  - Ossendorp FA
AD  - Department of Immunology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
FAU - Jager, Martine J
AU  - Jager MJ
AD  - Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The 
      Netherlands.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - EC 1.14.18.1 (Monophenol Monooxygenase)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Melanoma/genetics
MH  - Monophenol Monooxygenase/metabolism
MH  - Mice, Inbred C57BL
MH  - Macrophages/metabolism
MH  - Pigmentation
PMC - PMC10829805
COIS- Disclosure: S. Ma, None; R.V. Huis in't Veld, None; Y. Hao, None; Z. Gu, None; C. 
      Rich, (C); M.C. Gelmi, None; A.A. Mulder, None; P.A. van Veelen, None; T.K.H. Vu, 
      None; T. van Hall, None; F.A. Ossendorp, None; M.J. Jager, None
EDAT- 2024/01/25 18:42
MHDA- 2024/01/29 06:42
PMCR- 2024/01/25
CRDT- 2024/01/25 12:33
PHST- 2024/01/29 06:42 [medline]
PHST- 2024/01/25 18:42 [pubmed]
PHST- 2024/01/25 12:33 [entrez]
PHST- 2024/01/25 00:00 [pmc-release]
AID - 2793313 [pii]
AID - IOVS-23-38531 [pii]
AID - 10.1167/iovs.65.1.42 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2024 Jan 2;65(1):42. doi: 10.1167/iovs.65.1.42.