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CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma

CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma
CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma
Background Tumor infiltrating lymphocytes play a key role in antitumor responses; however, while several memory T cell subtypes have been reported in inflammatory and neoplastic conditions, the proportional representation of the different subsets of memory T cells and their functional significance in cancer is unclear. Keratinocyte skin cancer is one of the most common cancers globally, with cutaneous squamous cell cancer (cSCC) amongst the most frequent malignancies capable of metastasis.
Methods Memory T cell subsets were delineated in human cSCCs and, for comparison, in non-lesional skin and blood using flow cytometry. Immunohistochemistry was conducted to quantify CD103+ cells in primary human cSCCs which had metastasized (P-M) and primary cSCCs which had not metastasized (P-NM). TIMER2.0 (timer.cistrome.org) was used to analyze TCGA cancer survival data based on ITGAE expression. Immunofluorescence microscopy was performed to determine frequencies of CD8+CD103+ cells in P-M and P-NM cSCCs.
Results Despite inter-tumoral heterogeneity, most cSCC T cells were CCR7-/CD45RA- effector/resident memory (TEM/TRM) lymphocytes, with naive, CD45RA+/CCR7- (TEMRA), CCR7+/L-selectin+ central memory (TCM) and CCR7+/L-selectin- migratory memory (TMM) lymphocytes accounting for smaller T cell subsets. The cSCC CD8+ T cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood. These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103- TRMs in the tumor. CD103+ cells were more frequent P-M than P-NM cSCCs. Analysis of TCGA data demonstrated that high expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer, adrenocortical carcinoma and lower grade glioma. Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.
Conclusion These results highlight CD8+CD103+ TRMs as an important functional T cell subset associated with poorer clinical outcome in this cancer.
CD8-positive T-lymphocytes, T-Lymphocytes, lymphocytes, skin neoplasms, tumor microenvironment, tumor-infiltrating
Lai, Chester
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Coltart, George Stewart
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Shapanis, Andrew
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Healy, Conor
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Alabdulkareem, Ahmad
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Selvendran, Sara
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Theaker, Jeffrey
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Sommerlad, Matthew
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Rose-Zerilli, Matthew
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Al-Shamkhani, Aymen
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Healy, Eugene
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Lai, Chester
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Coltart, George Stewart
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Shapanis, Andrew
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Healy, Conor
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Alabdulkareem, Ahmad
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Selvendran, Sara
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Theaker, Jeffrey
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Sommerlad, Matthew
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Rose-Zerilli, Matthew
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Al-Shamkhani, Aymen
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Healy, Eugene
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Lai, Chester, Coltart, George Stewart, Shapanis, Andrew, Healy, Conor, Alabdulkareem, Ahmad, Selvendran, Sara, Theaker, Jeffrey, Sommerlad, Matthew, Rose-Zerilli, Matthew, Al-Shamkhani, Aymen and Healy, Eugene (2021) CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma. Journal for Immunotherapy of Cancer, 9 (1), [e001807]. (doi:10.1136/jitc-2020-001807).

Record type: Article

Abstract

Background Tumor infiltrating lymphocytes play a key role in antitumor responses; however, while several memory T cell subtypes have been reported in inflammatory and neoplastic conditions, the proportional representation of the different subsets of memory T cells and their functional significance in cancer is unclear. Keratinocyte skin cancer is one of the most common cancers globally, with cutaneous squamous cell cancer (cSCC) amongst the most frequent malignancies capable of metastasis.
Methods Memory T cell subsets were delineated in human cSCCs and, for comparison, in non-lesional skin and blood using flow cytometry. Immunohistochemistry was conducted to quantify CD103+ cells in primary human cSCCs which had metastasized (P-M) and primary cSCCs which had not metastasized (P-NM). TIMER2.0 (timer.cistrome.org) was used to analyze TCGA cancer survival data based on ITGAE expression. Immunofluorescence microscopy was performed to determine frequencies of CD8+CD103+ cells in P-M and P-NM cSCCs.
Results Despite inter-tumoral heterogeneity, most cSCC T cells were CCR7-/CD45RA- effector/resident memory (TEM/TRM) lymphocytes, with naive, CD45RA+/CCR7- (TEMRA), CCR7+/L-selectin+ central memory (TCM) and CCR7+/L-selectin- migratory memory (TMM) lymphocytes accounting for smaller T cell subsets. The cSCC CD8+ T cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood. These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103- TRMs in the tumor. CD103+ cells were more frequent P-M than P-NM cSCCs. Analysis of TCGA data demonstrated that high expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer, adrenocortical carcinoma and lower grade glioma. Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.
Conclusion These results highlight CD8+CD103+ TRMs as an important functional T cell subset associated with poorer clinical outcome in this cancer.

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Accepted/In Press date: 20 November 2020
e-pub ahead of print date: 21 January 2021
Additional Information: This is a Dermatology publication (i.e. not Respiratory)
Keywords: CD8-positive T-lymphocytes, T-Lymphocytes, lymphocytes, skin neoplasms, tumor microenvironment, tumor-infiltrating

Identifiers

Local EPrints ID: 445686
URI: http://eprints.soton.ac.uk/id/eprint/445686
PURE UUID: 4a09c31e-852d-45ba-b86b-080bf4ea7cd9
ORCID for George Stewart Coltart: ORCID iD orcid.org/0000-0001-7648-8741
ORCID for Andrew Shapanis: ORCID iD orcid.org/0000-0003-4147-6956
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 06 Jan 2021 17:37
Last modified: 04 Dec 2021 05:01

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Contributors

Author: Chester Lai
Author: George Stewart Coltart ORCID iD
Author: Andrew Shapanis ORCID iD
Author: Conor Healy
Author: Ahmad Alabdulkareem
Author: Sara Selvendran
Author: Jeffrey Theaker
Author: Matthew Sommerlad
Author: Eugene Healy

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