Cargando…
Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity
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 microenviro...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973420/ https://www.ncbi.nlm.nih.gov/pubmed/36860657 http://dx.doi.org/10.1158/2767-9764.CRC-22-0300 |
_version_ | 1784898519432167424 |
---|---|
author | Steinkamp, Mara P. Lagutina, Irina Brayer, Kathryn J. Schultz, Fred Burke, Danielle Pankratz, Vernon S. Adams, Sarah F. Hudson, Laurie G. Ness, Scott A. Wandinger-Ness, Angela |
author_facet | Steinkamp, Mara P. Lagutina, Irina Brayer, Kathryn J. Schultz, Fred Burke, Danielle Pankratz, Vernon S. Adams, Sarah F. Hudson, Laurie G. Ness, Scott A. Wandinger-Ness, Angela |
author_sort | Steinkamp, Mara P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9973420 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-99734202023-02-28 Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity Steinkamp, Mara P. Lagutina, Irina Brayer, Kathryn J. Schultz, Fred Burke, Danielle Pankratz, Vernon S. Adams, Sarah F. Hudson, Laurie G. Ness, Scott A. Wandinger-Ness, Angela Cancer Res Commun Research Article 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. American Association for Cancer Research 2023-02-22 /pmc/articles/PMC9973420/ /pubmed/36860657 http://dx.doi.org/10.1158/2767-9764.CRC-22-0300 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article Steinkamp, Mara P. Lagutina, Irina Brayer, Kathryn J. Schultz, Fred Burke, Danielle Pankratz, Vernon S. Adams, Sarah F. Hudson, Laurie G. Ness, Scott A. Wandinger-Ness, Angela Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title | Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title_full | Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title_fullStr | Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title_full_unstemmed | Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title_short | Humanized Patient-derived Xenograft Models of Disseminated Ovarian Cancer Recapitulate Key Aspects of the Tumor Immune Environment within the Peritoneal Cavity |
title_sort | humanized patient-derived xenograft models of disseminated ovarian cancer recapitulate key aspects of the tumor immune environment within the peritoneal cavity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973420/ https://www.ncbi.nlm.nih.gov/pubmed/36860657 http://dx.doi.org/10.1158/2767-9764.CRC-22-0300 |
work_keys_str_mv | AT steinkampmarap humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT lagutinairina humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT brayerkathrynj humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT schultzfred humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT burkedanielle humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT pankratzvernons humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT adamssarahf humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT hudsonlaurieg humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT nessscotta humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity AT wandingernessangela humanizedpatientderivedxenograftmodelsofdisseminatedovariancancerrecapitulatekeyaspectsofthetumorimmuneenvironmentwithintheperitonealcavity |