Organoid Modeling of the Tumor Immune Microenvironment

被引：1117

作者：

Neal, James T. ^{[1
,10
]}

Li, Xingnan ^{[1
]}

Zhu, Junjie ^{[2
]}

Giangarra, Valeria ^{[3
]}

Grzeskowiak, Caitlin L. ^{[1
]}

Ju, Jihang ^{[1
]}

Liu, Iris H. ^{[1
]}

Chiou, Shin-Heng ^{[4
]}

Salahudeen, Ameen A. ^{[1
]}

Smith, Amber R. ^{[1
]}

Deutsch, Brian C. ^{[1
]}

Liao, Lillian ^{[1
]}

Zemek, Allison J. ^{[7
]}

Zhao, Fan ^{[4
]}

Karlsson, Kasper ^{[1
]}

Schultz, Liora M. ^{[8
]}

Metzner, Thomas J. ^{[9
]}

Nadauld, Lincoln D. ^{[1
]}

Tseng, Yuen-Yi ^{[10
]}

Alkhairy, Sahar ^{[10
]}

Oh, Coyin ^{[10
]}

Keskula, Paula ^{[10
]}

Mendoza-Villanueva, Daniel ^{[11
]}

De La Vega, Francisco M. ^{[11
]}

Kunz, Pamela L. ^{[8
]}

Liao, Joseph C. ^{[9
]}

Leppert, John T. ^{[9
]}

Sunwoo, John B. ^{[12
]}

Sabatti, Chiara ^{[13
,14
]}

Boehm, Jesse S. ^{[10
]}

Hahn, William C. ^{[10
,15
]}

Zheng, Grace X. Y. ^{[3
]}

Davis, Mark M. ^{[4
,5
,6
]}

Kuo, Calvin J. ^{[1
]}

机构：

[1] Stanford Univ, Dept Med, Sch Med, Div Hematol, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Elect Engn, Sch Engn, Stanford, CA 94305 USA

[3] 10x Genom, Pleasanton, CA USA

[4] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA

[5] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA

[7] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA

[9] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA

[10] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[11] TOMA Biosci, Foster City, CA USA

[12] Stanford Univ, Sch Med, Dept Otolaryngol, Stanford, CA 94305 USA

[13] Stanford Univ, Sch Med, Dept Biomed Data Sci, Stanford, CA 94305 USA

[14] Stanford Univ, Dept Stat, Sch Humanities & Sci, Stanford, CA 94305 USA

[15] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

CELL | 2018年 / 175卷 / 07期

关键词：

T-CELL-RECEPTOR; CHECKPOINT BLOCKADE; ANTITUMOR IMMUNITY; PD-1; BLOCKADE; HUMAN COLON; NIVOLUMAB; EXPRESSION; LANDSCAPE; MELANOMA; THERAPY;

D O I：

10.1016/j.cell.2018.11.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDOTILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.

引用

页码：1972 / +

页数：33

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