Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer.
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Embargo End Date
ICR Authors
Authors
Muliaditan, T
Opzoomer, JW
Caron, J
Okesola, M
Kosti, P
Lall, S
Van Hemelrijck, M
Dazzi, F
Tutt, A
Grigoriadis, A
Gillett, CE
Madden, SF
Burchell, JM
Kordasti, S
Diebold, SS
Spicer, JF
Arnold, JN
Opzoomer, JW
Caron, J
Okesola, M
Kosti, P
Lall, S
Van Hemelrijck, M
Dazzi, F
Tutt, A
Grigoriadis, A
Gillett, CE
Madden, SF
Burchell, JM
Kordasti, S
Diebold, SS
Spicer, JF
Arnold, JN
Document Type
Journal Article
Date
2018-04-01
Date Accepted
2018-01-08
Abstract
Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immunosuppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited antitumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinemia, as an immune checkpoint blockade therapy for the treatment of cancer.Experimental Design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray, and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations.Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8+ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA-sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compare the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably with PD-1 blockade in preclinical models.Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy. Clin Cancer Res; 24(7); 1617-28. ©2018 AACR.
Citation
Clinical Cancer Research, 2018, 24 (7), pp. 1617 - 1628
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Directorate Breast Canc