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posted on 2024-05-06, 10:20 authored by Mara P. Steinkamp, Irina Lagutina, Kathryn J. Brayer, Fred Schultz, Danielle Burke, Vernon S. Pankratz, Sarah F. Adams, Laurie G. Hudson, Scott A. Ness, Angela Wandinger-Ness Survival time is reduced in huNBSGW PDX models. A, huNBSGW PDX3, 9, and 18 were engrafted with the same pooled donor CD34+ cells. Survival time was PDX dependent with PDX3 and 9 having a shorter survival time compared with PDX18. Survival curves are significantly different between huPDX and non-huPDX for all three PDX models (P < 0.025, log-rank test). For all PDX models, n = 3 mice/group for huPDX and non-huPDX. B, Solid tumor mass (in grams) of huPDX and non-huPDX at necropsy. Bars are the average tumor burden, error bars are SEM. Measures for individual mice are shown as black dots (n = 2–3 per group). C, Ascites fluid volume at necropsy. The ascites fluid volume trended higher in non-huPDX for PDX3 and PDX9, but was only significantly different for PDX9. Statistical analysis for B and C used unpaired t tests to compare huPDX versus non-huPDX values for each PDX line.
Funding
HHS | NIH | National Cancer Institute (NCI)
UNM | School of Medicine, University of New Mexico (UNM SOM)
History
ARTICLE 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.
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.
