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M1 hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer

M1 hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer
M1 hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer
Background: the role of Tumour-Associated Macrophages (TAMs) in determining the outcome between the anti-tumour effects of the adaptive immune system and the tumour’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumour micro-environment. Depending on how macrophages are activated, they may adopt so-called M1-like, anti-tumour or M2-like, pro-tumour profiles. In many solid tumours, a dominance of M2-like macrophages is associated with poor outcomes but in some tumour types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the inter-relationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer.
Methods: macrophages from matched lung (NTAMs) and tumour samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (CXCL9) or M2-like (MMP12) functions was confirmed by confocal microscopy. Immunohistochemistry related the distribution of TAM transcriptomic signatures to density of CD8+ tissue-resident memory T cells (TRM) in tumours and survival data from an independent cohort of 393 lung cancer patients
Results: TAMs have significantly different transcriptomic profiles from NTAMs with >1000 differentially expressed genes. TAMs displayed a strong M2-like signature with no significant variation between patients. However, single-cell RNA-seq supported by immuno-stained cells revealed that additionally, in 25% of patients the M2-like TAMs also co-expressed a strong/hot M1-like signature (M1hot). Importantly, there was a strong association between the density of M1hot TAMs and TRM cells in tumours that was in turn linked to better survival. Our data suggests a mechanism by which M1hot TAMs may recruit TRM cells via CXCL9 expression and sustain them by making available more of the essential fatty acids on which TRM depend.
Conclusions: we showed that in early lung cancer, expression of M1-like and M2-like gene signatures are not mutually exclusive since the same TAMs can simultaneously display both gene-expression profiles. The presence of M1hot TAMs was associated with a strong TRM tumour-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive anti-tumour responses.
immunity, immunity, innate, lung neoplasms, macrophages
Garrido Martin, Eva
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Mellows, Toby
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Chee, Serena Jamie Tzu Wen
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Cazaly, Angelica M
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Seumois, Gregory
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Clarke, James Ian
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Wood, Oliver
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Ganesan, A.
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King, Emma
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Hedrick, Catherine C.
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Alzetani, Aiman
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Thomas, Gareth
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Friedmann, Peter
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Ottensmeier, Christian
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Vijayanand, Pandurangan
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Sanchez-Elsner, Tilman
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Garrido Martin, Eva
bba99077-0684-4516-8a15-e80409c12734
Mellows, Toby
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Chee, Serena Jamie Tzu Wen
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Cazaly, Angelica M
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Seumois, Gregory
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Clarke, James Ian
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Wood, Oliver
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Ganesan, A.
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King, Emma
d85e0e8f-7295-4912-9052-646a790d99db
Hedrick, Catherine C.
c443d2f1-5b9d-4298-b2d6-4729c2fdb7f4
Alzetani, Aiman
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Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Friedmann, Peter
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Ottensmeier, Christian
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Vijayanand, Pandurangan
79514f33-66cf-47cc-a8fa-46bbfc21b7d1
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d

Garrido Martin, Eva, Mellows, Toby, Chee, Serena Jamie Tzu Wen, Cazaly, Angelica M, Seumois, Gregory, Clarke, James Ian, Wood, Oliver, Ganesan, A., King, Emma, Hedrick, Catherine C., Alzetani, Aiman, Thomas, Gareth, Friedmann, Peter, Ottensmeier, Christian, Vijayanand, Pandurangan and Sanchez-Elsner, Tilman (2020) M1 hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer. Journal for Immunotherapy of Cancer, 8 (2), [e000778]. (doi:10.1136/jitc-2020-000778).

Record type: Article

Abstract

Background: the role of Tumour-Associated Macrophages (TAMs) in determining the outcome between the anti-tumour effects of the adaptive immune system and the tumour’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumour micro-environment. Depending on how macrophages are activated, they may adopt so-called M1-like, anti-tumour or M2-like, pro-tumour profiles. In many solid tumours, a dominance of M2-like macrophages is associated with poor outcomes but in some tumour types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the inter-relationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer.
Methods: macrophages from matched lung (NTAMs) and tumour samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (CXCL9) or M2-like (MMP12) functions was confirmed by confocal microscopy. Immunohistochemistry related the distribution of TAM transcriptomic signatures to density of CD8+ tissue-resident memory T cells (TRM) in tumours and survival data from an independent cohort of 393 lung cancer patients
Results: TAMs have significantly different transcriptomic profiles from NTAMs with >1000 differentially expressed genes. TAMs displayed a strong M2-like signature with no significant variation between patients. However, single-cell RNA-seq supported by immuno-stained cells revealed that additionally, in 25% of patients the M2-like TAMs also co-expressed a strong/hot M1-like signature (M1hot). Importantly, there was a strong association between the density of M1hot TAMs and TRM cells in tumours that was in turn linked to better survival. Our data suggests a mechanism by which M1hot TAMs may recruit TRM cells via CXCL9 expression and sustain them by making available more of the essential fatty acids on which TRM depend.
Conclusions: we showed that in early lung cancer, expression of M1-like and M2-like gene signatures are not mutually exclusive since the same TAMs can simultaneously display both gene-expression profiles. The presence of M1hot TAMs was associated with a strong TRM tumour-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1hot phenotype are likely to augment the adaptive anti-tumour responses.

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Garrido-Martin et al 2020 Main Manuscript - Accepted Manuscript
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Accepted/In Press date: 26 May 2020
e-pub ahead of print date: 21 July 2020
Published date: 21 July 2020
Keywords: immunity, immunity, innate, lung neoplasms, macrophages

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Local EPrints ID: 441871
URI: http://eprints.soton.ac.uk/id/eprint/441871
PURE UUID: 5a445a28-4ce0-4908-b1d3-e652df181257
ORCID for Tilman Sanchez-Elsner: ORCID iD orcid.org/0000-0003-1915-2410

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Date deposited: 01 Jul 2020 16:30
Last modified: 18 Feb 2021 17:09

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Contributors

Author: Eva Garrido Martin
Author: Toby Mellows
Author: Serena Jamie Tzu Wen Chee
Author: Angelica M Cazaly
Author: Gregory Seumois
Author: James Ian Clarke
Author: Oliver Wood
Author: A. Ganesan
Author: Emma King
Author: Catherine C. Hedrick
Author: Aiman Alzetani
Author: Gareth Thomas
Author: Peter Friedmann
Author: Pandurangan Vijayanand

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