TY - JOUR
T1 - Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models
AU - Rosato, Roberto R.
AU - Dávila-González, Daniel
AU - Choi, Dong Soon
AU - Qian, Wei
AU - Chen, Wen
AU - Kozielski, Anthony J.
AU - Wong, Helen
AU - Dave, Bhuvanesh
AU - Chang, Jenny C.
N1 - Funding Information:
This research was supported by National Cancer Institute grants R01 CA138197 and U54 CA149196 from the National Institutes of Health, Golfers Against Cancer, the Breast Cancer Research Foundation, Causes for a Cure, Team Tiara, the Emily W. Herrman Cancer Research Laboratory, Department of Defense Innovator Expansion Award BC104158, and Komen for Cure grant KG 081694 (to JCC). None of the funding sources had any role in the design of the study, the analysis or interpretation of data, or the writing of the present manuscript.
Funding Information:
The RNA-seq data were generated and analyzed by the Genome Sequencing Facility of Greehey Children’s Cancer Research Institute at the University of Texas Health San Antonio. We thank Dr. Zhao Lai for RNA-seq assistance and Hung-I Chen and Dr. Yidong Chen for RNA-seq data analysis. Low-resolution HLA typing was performed by the transplant immunology laboratory at Houston Methodist Hospital, Houston, TX, USA. DDG is grateful for support from the Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico, and Consejo Nacional de Ciencia y Tecnología, Mexico (CONACyT 490148/278957). The authors acknowledge the help provided by the Flow Cytometry and Comparative Medicine core facilities at the Houston Methodist Research Institute. DDG is a current graduate student at the Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/9/5
Y1 - 2018/9/5
N2 - Background: Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models. Methods: To circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγ null (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3-4-week-old mice. After both PDXs and melanoma cell xenografts reached ~150-200mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action. Results: Human CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models. Conclusions: This study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.
AB - Background: Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models. Methods: To circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγ null (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3-4-week-old mice. After both PDXs and melanoma cell xenografts reached ~150-200mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action. Results: Human CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models. Conclusions: This study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.
KW - Anti-PD-1
KW - Humanized mouse model
KW - Immunotherapy
KW - PD-L1
KW - TNBC
KW - Triple-negative breast cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85052921551&partnerID=8YFLogxK
U2 - 10.1186/s13058-018-1037-4
DO - 10.1186/s13058-018-1037-4
M3 - Article
C2 - 30185216
AN - SCOPUS:85052921551
SN - 1465-5411
VL - 20
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 108
ER -