Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity

Wenqun Zhong; Youtao Lu; Xuexiang Han; Jingbo Yang; Zhiyuan Qin; Wei Zhang; Ziyan Yu; Bin Wu; Shujing Liu; Wei Xu; Cathy Zheng; Lynn M. Schuchter; Giorgos C. Karakousis; Tara C. Mitchell; Ravi Amaravadi; Ahron J. Flowers; Phyllis A. Gimotty; Min Xiao; Gordon Mills; Meenhard Herlyn; Haidong Dong; Michael J. Mitchell; Junhyong Kim; Xiaowei Xu; Wei Guo

doi:10.1016/j.celrep.2023.113224

Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity

Wenqun Zhong, Youtao Lu, Xuexiang Han, Jingbo Yang, Zhiyuan Qin, Wei Zhang, Ziyan Yu, Bin Wu, Shujing Liu, Wei Xu, Cathy Zheng, Lynn M. Schuchter, Giorgos C. Karakousis, Tara C. Mitchell, Ravi Amaravadi, Ahron J. Flowers, Phyllis A. Gimotty, Min Xiao, Gordon Mills, Meenhard HerlynHaidong Dong, Michael J. Mitchell, Junhyong Kim, Xiaowei Xu, Wei Guo

Urology

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

Abstract

Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8⁺ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8⁺ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8⁺ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.

Original language	English (US)
Article number	113224
Journal	Cell reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113224
State	Published - Oct 31 2023

Keywords

CP: Cancer
CP: Immunology
exosome
immunotherapy
programmed cell death ligand 1
tumor-associated macrophages

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.113224

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Zhong, W., Lu, Y., Han, X., Yang, J., Qin, Z., Zhang, W., Yu, Z., Wu, B., Liu, S., Xu, W., Zheng, C., Schuchter, L. M., Karakousis, G. C., Mitchell, T. C., Amaravadi, R., Flowers, A. J., Gimotty, P. A., Xiao, M., Mills, G., ... Guo, W. (2023). Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity. Cell reports, 42(10), Article 113224. https://doi.org/10.1016/j.celrep.2023.113224

Zhong, W, Lu, Y, Han, X, Yang, J, Qin, Z, Zhang, W, Yu, Z, Wu, B, Liu, S, Xu, W, Zheng, C, Schuchter, LM, Karakousis, GC, Mitchell, TC, Amaravadi, R, Flowers, AJ, Gimotty, PA, Xiao, M, Mills, G, Herlyn, M, Dong, H, Mitchell, MJ, Kim, J, Xu, X & Guo, W 2023, 'Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity', Cell reports, vol. 42, no. 10, 113224. https://doi.org/10.1016/j.celrep.2023.113224

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title = "Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity",

abstract = "Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.",

keywords = "CP: Cancer, CP: Immunology, exosome, immunotherapy, programmed cell death ligand 1, tumor-associated macrophages",

author = "Wenqun Zhong and Youtao Lu and Xuexiang Han and Jingbo Yang and Zhiyuan Qin and Wei Zhang and Ziyan Yu and Bin Wu and Shujing Liu and Wei Xu and Cathy Zheng and Schuchter, {Lynn M.} and Karakousis, {Giorgos C.} and Mitchell, {Tara C.} and Ravi Amaravadi and Flowers, {Ahron J.} and Gimotty, {Phyllis A.} and Min Xiao and Gordon Mills and Meenhard Herlyn and Haidong Dong and Mitchell, {Michael J.} and Junhyong Kim and Xiaowei Xu and Wei Guo",

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doi = "10.1016/j.celrep.2023.113224",

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AU - Zhong, Wenqun

AU - Lu, Youtao

AU - Han, Xuexiang

AU - Yang, Jingbo

AU - Qin, Zhiyuan

AU - Zhang, Wei

AU - Yu, Ziyan

AU - Wu, Bin

AU - Liu, Shujing

AU - Xu, Wei

AU - Zheng, Cathy

AU - Schuchter, Lynn M.

AU - Karakousis, Giorgos C.

AU - Mitchell, Tara C.

AU - Amaravadi, Ravi

AU - Flowers, Ahron J.

AU - Gimotty, Phyllis A.

AU - Xiao, Min

AU - Mills, Gordon

AU - Herlyn, Meenhard

AU - Dong, Haidong

AU - Mitchell, Michael J.

AU - Kim, Junhyong

AU - Xu, Xiaowei

AU - Guo, Wei

PY - 2023/10/31

Y1 - 2023/10/31

N2 - Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.

AB - Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.

KW - CP: Cancer

KW - CP: Immunology

KW - exosome

KW - immunotherapy

KW - programmed cell death ligand 1

KW - tumor-associated macrophages

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SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 10

M1 - 113224

ER -

Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity

Abstract

Keywords

ASJC Scopus subject areas

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