Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity.

Autor:	Steinkamp MP; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico., Lagutina I; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico., Brayer KJ; Analytical and Translational Genomics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico., Schultz F; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico., Burke D; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico., Pankratz VS; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.; Biostatistics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico., Adams SF; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.; Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico., Hudson LG; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.; Department of Pharmaceutical Sciences, University of New Mexico School of Medicine, Albuquerque, New Mexico., Ness SA; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico., Wandinger-Ness A; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico.; Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Feb 22; Vol. 3 (2), pp. 309-324. Date of Electronic Publication: 2023 Feb 22 (Print Publication: 2023).
DOI:	10.1158/2767-9764.CRC-22-0300
Abstrakt:	The importance of the immune microenvironment in ovarian cancer progression, metastasis, and response to therapies has become increasingly clear, especially with the new emphasis on immunotherapies. To leverage the power of patient-derived xenograft (PDX) models within a humanized immune microenvironment, three ovarian cancer PDXs were grown in humanized NBSGW (huNBSGW) mice engrafted with human CD34 + cord blood-derived hematopoietic stem cells. Analysis of cytokine levels in the ascites fluid and identification of infiltrating immune cells in the tumors demonstrated that these humanized PDX (huPDX) established an immune tumor microenvironment similar to what has been reported for patients with ovarian cancer. The lack of human myeloid cell differentiation has been a major setback for humanized mouse models, but our analysis shows that PDX engraftment increases the human myeloid population in the peripheral blood. Analysis of cytokines within the ascites fluid of huPDX revealed high levels of human M-CSF, a key myeloid differentiation factor as well as other elevated cytokines that have previously been identified in ovarian cancer patient ascites fluid including those involved in immune cell differentiation and recruitment. Human tumor-associated macrophages and tumor-infiltrating lymphocytes were detected within the tumors of humanized mice, demonstrating immune cell recruitment to tumors. Comparison of the three huPDX revealed certain differences in cytokine signatures and in the extent of immune cell recruitment. Our studies show that huNBSGW PDX models reconstitute important aspects of the ovarian cancer immune tumor microenvironment, which may recommend these models for preclinical therapeutic trials. Significance: huPDX models are ideal preclinical models for testing novel therapies. They reflect the genetic heterogeneity of the patient population, enhance human myeloid differentiation, and recruit immune cells to the tumor microenvironment. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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