Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy

Minan Wang; Li Chin Yao; Mingshan Cheng; Danying Cai; Jan Martinek; Chong-Xian Pan; Wei Shi; Ai Hong Ma; Ralph W deVere White; Susan Airhart; Edison T. Liu; Jacques Banchereau; Michael A. Brehm; Dale L. Greiner; Leonard D. Shultz; Karolina Palucka; James G. Keck

doi:10.1096/fj.201700740R

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy

Minan Wang, Li Chin Yao, Mingshan Cheng, Danying Cai, Jan Martinek, Chong-Xian Pan, Wei Shi, Ai Hong Ma, Ralph W deVere White, Susan Airhart, Edison T. Liu, Jacques Banchereau, Michael A. Brehm, Dale L. Greiner, Leonard D. Shultz, Karolina Palucka, James G. Keck

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-Prkdc^scidIL2rg^tm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34⁺ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.

Original language	English (US)
Pages (from-to)	1537-1549
Number of pages	13
Journal	FASEB Journal
Volume	32
Issue number	3
DOIs	https://doi.org/10.1096/fj.201700740R
State	Published - Mar 1 2018

Keywords

Checkpoint inhibitor
Mouse model
Patient-derived xenograft
Pembrolizumab

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

Access to Document

10.1096/fj.201700740R

Fingerprint Dive into the research topics of 'Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy'. Together they form a unique fingerprint.

Cite this

Wang, M., Yao, L. C., Cheng, M., Cai, D., Martinek, J., Pan, C-X., Shi, W., Ma, A. H., deVere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., & Keck, J. G. (2018). Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. FASEB Journal, 32(3), 1537-1549. https://doi.org/10.1096/fj.201700740R

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. / Wang, Minan; Yao, Li Chin; Cheng, Mingshan; Cai, Danying; Martinek, Jan; Pan, Chong-Xian; Shi, Wei; Ma, Ai Hong; deVere White, Ralph W; Airhart, Susan; Liu, Edison T.; Banchereau, Jacques; Brehm, Michael A.; Greiner, Dale L.; Shultz, Leonard D.; Palucka, Karolina; Keck, James G.

In: FASEB Journal, Vol. 32, No. 3, 01.03.2018, p. 1537-1549.

Research output: Contribution to journal › Article › peer-review

Wang, Minan ; Yao, Li Chin ; Cheng, Mingshan ; Cai, Danying ; Martinek, Jan ; Pan, Chong-Xian ; Shi, Wei ; Ma, Ai Hong ; deVere White, Ralph W ; Airhart, Susan ; Liu, Edison T. ; Banchereau, Jacques ; Brehm, Michael A. ; Greiner, Dale L. ; Shultz, Leonard D. ; Palucka, Karolina ; Keck, James G. / Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. In: FASEB Journal. 2018 ; Vol. 32, No. 3. pp. 1537-1549.

@article{9548094863de451e84570d84af6a906a,

title = "Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy",

abstract = "Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.",

keywords = "Checkpoint inhibitor, Mouse model, Patient-derived xenograft, Pembrolizumab",

author = "Minan Wang and Yao, {Li Chin} and Mingshan Cheng and Danying Cai and Jan Martinek and Chong-Xian Pan and Wei Shi and Ma, {Ai Hong} and {deVere White}, {Ralph W} and Susan Airhart and Liu, {Edison T.} and Jacques Banchereau and Brehm, {Michael A.} and Greiner, {Dale L.} and Shultz, {Leonard D.} and Karolina Palucka and Keck, {James G.}",

year = "2018",

month = mar,

day = "1",

doi = "10.1096/fj.201700740R",

language = "English (US)",

volume = "32",

pages = "1537--1549",

journal = "FASEB Journal",

issn = "0892-6638",

publisher = "FASEB",

number = "3",

}

TY - JOUR

T1 - Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy

AU - Wang, Minan

AU - Yao, Li Chin

AU - Cheng, Mingshan

AU - Cai, Danying

AU - Martinek, Jan

AU - Pan, Chong-Xian

AU - Shi, Wei

AU - Ma, Ai Hong

AU - deVere White, Ralph W

AU - Airhart, Susan

AU - Liu, Edison T.

AU - Banchereau, Jacques

AU - Brehm, Michael A.

AU - Greiner, Dale L.

AU - Shultz, Leonard D.

AU - Palucka, Karolina

AU - Keck, James G.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.

AB - Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into themechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patientderived xenografts [PDX;non-small cell lungcancer (NSCLC), sarcoma, bladder cancer, andtriple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSGmice. Treatmentwith pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition inbothCDXandPDXtumorsinHuNSGbut not inNSGmice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearingHuNSG mice may represent an important, newmodel for preclinical immunotherapy research.

KW - Checkpoint inhibitor

KW - Mouse model

KW - Patient-derived xenograft

KW - Pembrolizumab

UR - http://www.scopus.com/inward/record.url?scp=85043580332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043580332&partnerID=8YFLogxK

U2 - 10.1096/fj.201700740R

DO - 10.1096/fj.201700740R

M3 - Article

C2 - 29146734

AN - SCOPUS:85043580332

VL - 32

SP - 1537

EP - 1549

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 3

ER -