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

Author:

Steinkamp Mara P.12ORCID,Lagutina Irina2ORCID,Brayer Kathryn J.3ORCID,Schultz Fred1ORCID,Burke Danielle1ORCID,Pankratz Vernon S.45ORCID,Adams Sarah F.26ORCID,Hudson Laurie G.27ORCID,Ness Scott A.28ORCID,Wandinger-Ness Angela12ORCID

Affiliation:

1. 1Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico.

2. 2Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico

3. 3Analytical and Translational Genomics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.

4. 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.

5. 5Biostatistics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico.

6. 6Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico.

7. 7Department of Pharmaceutical Sciences, University of New Mexico School of Medicine, Albuquerque, New Mexico.

8. 8Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico.

Abstract

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.

Funder

HHS | NIH | National Cancer Institute

UNM | School of Medicine, University of New Mexico

Publisher

American Association for Cancer Research (AACR)

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