Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Single-Cell Profiling Reveals Immune-Based Mechanisms Underlying the Tumor Radiosensitization by a Novel Mn Porphyrin Clinical Candidate, MnTnBuOE-2-PyP5+ (BMX-001)

Sun Up Noh
ORCID logo ,
Jinyeong Lim
,
Sung-Won Shin
,
Yeeun Kim
,
Woong-Yang Park
ORCID logo ,
Ines Batinic-Haberle
ORCID logo ,
Changhoon Choi
* ORCID logo ,
Won Park
*
Version 1 : Received: 5 February 2024 / Approved: 6 February 2024 / Online: 6 February 2024 (09:43:28 CET)

A peer-reviewed article of this Preprint also exists.

Noh, S.U.; Lim, J.; Shin, S.-W.; Kim, Y.; Park, W.-Y.; Batinic-Haberle, I.; Choi, C.; Park, W. Single-Cell Profiling Reveals Immune-Based Mechanisms Underlying Tumor Radiosensitization by a Novel Mn Porphyrin Clinical Candidate, MnTnBuOE-2-PyP5+ (BMX-001). Antioxidants 2024, 13, 477. Noh, S.U.; Lim, J.; Shin, S.-W.; Kim, Y.; Park, W.-Y.; Batinic-Haberle, I.; Choi, C.; Park, W. Single-Cell Profiling Reveals Immune-Based Mechanisms Underlying Tumor Radiosensitization by a Novel Mn Porphyrin Clinical Candidate, MnTnBuOE-2-PyP5+ (BMX-001). Antioxidants 2024, 13, 477.

Abstract

Manganese porphyrins reportedly exhibit synergic effects when combined with irradiation. However, an in-depth understanding of intratumoral heterogeneity and immune pathways, as affected by Mn porphyrins, remains limited. Here, we explored the mechanisms underlying immunomodulation of a clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001, MnBuOE), using single-cell analysis in murine carcinoma model. Mice bearing 4T1 tumors were divided into 4 groups: control, MnBuOE, radiotherapy (RT), combined MnBuOE and radiotherapy (MnBuOE/RT). In epithelial cells, epithelial-mesenchymal transition, TNF-α signaling via NF-кB, angiogenesis, and hypoxia-related genes were significantly downregulated in the MnBuOE/RT compared to the RT. All subtypes of cancer-associated fibroblasts (CAFs) were clearly reduced in MnBuOE and MnBuOE/RT. Inhibitory receptor-ligand interactions, in which epithelial cells and CAFs interacted with CD8+ T cells, were significantly lower in the MnBuOE/RT than in the RT. Trajectory analysis showed that DC maturation-associated markers were increased in MnBuOE/RT. M1 macrophages were significantly increased in the MnBuOE/RT compared to the RT, whereas myeloid-derived suppressor cells were decreased. CellChat analysis showed that the number of cell-cell communications was the lowest in the MnBuOE/RT. Our study is the first to provide evidence for the combined radiotherapy with a novel Mn porphyrin clinical candidate, BMX-001 from the perspective of each cell-type within the tumor microenvironment.

Keywords

Mn porphyrin clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001, MnBuOE); Single-cell RNA sequencing; Tumor heterogeneity; Tumor microenvironment; Radiotherapy; Tumor radiosensitization

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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