figure
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 Analysis of RNA-seq data comparing ovarian cancer patient samples to non-huPDX samples highlights the importance of immune cells in the patient samples. A, Of the differentially expressed genes that show significantly lower expression in non-huPDX samples (orange) compared with primary ovarian cancer ascites cells and primary ovarian cancer tumor samples, 43% are immune-related genes (highlighted in purple). A list of the differentially expressed genes (left) can also be found in Supplementary Table S3. B and C, GSEA comparing primary ascites (n = 8) and primary tumors (n = 14) shows enrichment in genes associated with IFNγ stimulation in primary ascites. D–G, Deconvolution analysis of the ovarian cancer RNA-seq dataset using Carcinoma Ecotyper to estimate the abundance of monocytes/macrophages (D), CD4+ T cells (E), CD8+ T cells (F), and cancer epithelial cells (G). Deconvolution can detect the absence of immune cells in the PDX samples. Note that certain predicted states (S) may not be specific to immune cells since they are abundant in the immunocompromised non-huPDX samples (e.g., monocyte/macrophage states S07–S09 and CD4+ T-cell states S03, S05, and S06). G, The relative abundance of epithelial states is also altered in the non-huPDX with a significant reduction in states S02–S04 based on an unpaired t test (P < 0.0001, P < 0.009, P < 0.005, respectively).
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.
