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Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-...

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Autores principales: Marín-Jiménez, Juan A., Capasso, Anna, Lewis, Matthew S., Bagby, Stacey M., Hartman, Sarah J., Shulman, Jeremy, Navarro, Natalie M., Yu, Hui, Rivard, Chris J., Wang, Xiaoguang, Barkow, Jessica C., Geng, Degui, Kar, Adwitiya, Yingst, Ashley, Tufa, Dejene M., Dolan, James T., Blatchford, Patrick J., Freed, Brian M., Torres, Raul M., Davila, Eduardo, Slansky, Jill E., Pelanda, Roberta, Eckhardt, S. Gail, Messersmith, Wells A., Diamond, Jennifer R., Lieu, Christopher H., Verneris, Michael R., Wang, Jing H., Kiseljak-Vassiliades, Katja, Pitts, Todd M., Lang, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040953/
https://www.ncbi.nlm.nih.gov/pubmed/33854497
http://dx.doi.org/10.3389/fimmu.2021.607282
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author Marín-Jiménez, Juan A.
Capasso, Anna
Lewis, Matthew S.
Bagby, Stacey M.
Hartman, Sarah J.
Shulman, Jeremy
Navarro, Natalie M.
Yu, Hui
Rivard, Chris J.
Wang, Xiaoguang
Barkow, Jessica C.
Geng, Degui
Kar, Adwitiya
Yingst, Ashley
Tufa, Dejene M.
Dolan, James T.
Blatchford, Patrick J.
Freed, Brian M.
Torres, Raul M.
Davila, Eduardo
Slansky, Jill E.
Pelanda, Roberta
Eckhardt, S. Gail
Messersmith, Wells A.
Diamond, Jennifer R.
Lieu, Christopher H.
Verneris, Michael R.
Wang, Jing H.
Kiseljak-Vassiliades, Katja
Pitts, Todd M.
Lang, Julie
author_facet Marín-Jiménez, Juan A.
Capasso, Anna
Lewis, Matthew S.
Bagby, Stacey M.
Hartman, Sarah J.
Shulman, Jeremy
Navarro, Natalie M.
Yu, Hui
Rivard, Chris J.
Wang, Xiaoguang
Barkow, Jessica C.
Geng, Degui
Kar, Adwitiya
Yingst, Ashley
Tufa, Dejene M.
Dolan, James T.
Blatchford, Patrick J.
Freed, Brian M.
Torres, Raul M.
Davila, Eduardo
Slansky, Jill E.
Pelanda, Roberta
Eckhardt, S. Gail
Messersmith, Wells A.
Diamond, Jennifer R.
Lieu, Christopher H.
Verneris, Michael R.
Wang, Jing H.
Kiseljak-Vassiliades, Katja
Pitts, Todd M.
Lang, Julie
author_sort Marín-Jiménez, Juan A.
collection PubMed
description Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2(null)Il2rγ(null)SIRPα(NOD) (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
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spelling pubmed-80409532021-04-13 Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes Marín-Jiménez, Juan A. Capasso, Anna Lewis, Matthew S. Bagby, Stacey M. Hartman, Sarah J. Shulman, Jeremy Navarro, Natalie M. Yu, Hui Rivard, Chris J. Wang, Xiaoguang Barkow, Jessica C. Geng, Degui Kar, Adwitiya Yingst, Ashley Tufa, Dejene M. Dolan, James T. Blatchford, Patrick J. Freed, Brian M. Torres, Raul M. Davila, Eduardo Slansky, Jill E. Pelanda, Roberta Eckhardt, S. Gail Messersmith, Wells A. Diamond, Jennifer R. Lieu, Christopher H. Verneris, Michael R. Wang, Jing H. Kiseljak-Vassiliades, Katja Pitts, Todd M. Lang, Julie Front Immunol Immunology Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2(null)Il2rγ(null)SIRPα(NOD) (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis. Frontiers Media S.A. 2021-03-29 /pmc/articles/PMC8040953/ /pubmed/33854497 http://dx.doi.org/10.3389/fimmu.2021.607282 Text en Copyright © 2021 Marín-Jiménez, Capasso, Lewis, Bagby, Hartman, Shulman, Navarro, Yu, Rivard, Wang, Barkow, Geng, Kar, Yingst, Tufa, Dolan, Blatchford, Freed, Torres, Davila, Slansky, Pelanda, Eckhardt, Messersmith, Diamond, Lieu, Verneris, Wang, Kiseljak-Vassiliades, Pitts and Lang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Marín-Jiménez, Juan A.
Capasso, Anna
Lewis, Matthew S.
Bagby, Stacey M.
Hartman, Sarah J.
Shulman, Jeremy
Navarro, Natalie M.
Yu, Hui
Rivard, Chris J.
Wang, Xiaoguang
Barkow, Jessica C.
Geng, Degui
Kar, Adwitiya
Yingst, Ashley
Tufa, Dejene M.
Dolan, James T.
Blatchford, Patrick J.
Freed, Brian M.
Torres, Raul M.
Davila, Eduardo
Slansky, Jill E.
Pelanda, Roberta
Eckhardt, S. Gail
Messersmith, Wells A.
Diamond, Jennifer R.
Lieu, Christopher H.
Verneris, Michael R.
Wang, Jing H.
Kiseljak-Vassiliades, Katja
Pitts, Todd M.
Lang, Julie
Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title_full Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title_fullStr Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title_full_unstemmed Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title_short Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes
title_sort testing cancer immunotherapy in a human immune system mouse model: correlating treatment responses to human chimerism, therapeutic variables and immune cell phenotypes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040953/
https://www.ncbi.nlm.nih.gov/pubmed/33854497
http://dx.doi.org/10.3389/fimmu.2021.607282
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