Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer

被引：197

作者：

Kersten, Kelly ^{[1
,2
,8
]}

Hu, Kenneth H. ^{[1
,2
,8
]}

Combes, Alexis J. ^{[1
,2
,3
]}

Samad, Bushra ^{[1
,2
,3
]}

Harwin, Tory ^{[1
,2
]}

Ray, Arja ^{[1
,2
]}

Rao, Arjun Arkal ^{[1
,2
,3
]}

Cai, En ^{[1
,2
]}

Marchuk, Kyle ^{[3
]}

Artichoker, Jordan ^{[3
]}

Courau, Tristan ^{[1
,2
,3
]}

Shi, Quanming ^{[4
]}

Belk, Julia ^{[5
]}

Satpathy, Ansuman T. ^{[6
,7
]}

Krummel, Matthew F. ^{[1
,2
,3
,8
]}

机构：

[1] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, ImmunoX Initiat, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, UCSF CoLabs, San Francisco, CA 94143 USA

[4] Stanford Univ, Dept Personal Dynam Regulomes, Sch Med, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[7] Gladstone UCSF Inst Genom Immunol, San Francisco, CA 94158 USA

[8] Parker Inst Canc Immunotherapy, San Francisco, CA 94129 USA

来源：

CANCER CELL | 2022年 / 40卷 / 06期

基金：

美国国家科学基金会;

关键词：

DENDRITIC CELLS; TUMOR RESPONSES; IMMUNE CELLS; PD-1; SEQ; DIFFERENTIATION; LANDSCAPE; MICROENVIRONMENT; DYSFUNCTION; TRAFFICKING;

D O I：

10.1016/j.ccell.2022.05.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages (TAMs) and exhausted T cells (T-ex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAMs reduces exhaustion programs in tumor-infiltrating CD8(+) T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that T-ex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8(+) T cells engage in unique, long-lasting, antigen-specific synaptic interactions that fail to activate T cells but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.

引用

页码：624 / +

页数：25

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