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OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential

OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential
OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential
Purpose: Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.
Experimental Design: Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. Results: FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (p<0.0001, n=86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4+ (p=0.005, n=10 tumors) and CD8+ T cells (p=0.043, n=9 tumors) and inhibited interferon-γ secretion by tumoral effector T cells (p=0.0186, n=11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (p<0.0001, n=15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4+ lymphocyte proliferation (p=0.0098, n=10 tumors). Tregs and OX40+ lymphocytes were more abundant in primary cSCCs which metastasized than in primary cSCCs which had not metastasized (n=48 and n=49 tumors respectively).
Conclusions: Tregs in cSCCs suppress effector T cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis.
1078-0432
1-42
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
August, Suzannah
1fc940e8-45d7-46b0-8da7-efdfcfcbebbb
Albibas, Amel
3de1249c-580c-42e3-9fde-ca82b40b0185
Behar, Ramnik
cae7deb5-66d5-4f1b-9b21-751a614345a3
Cho, Shin-Young
d78bd886-a2a3-4a92-b484-6e0b41aa268d
Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Theaker, Jeff
2e0133cc-197b-479a-9465-458e534deb63
Macleod, Amanda S.
306d3cbc-fbda-4f18-83eb-5c4defcd943a
French, Ruth
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Glennie, Martin
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Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
August, Suzannah
1fc940e8-45d7-46b0-8da7-efdfcfcbebbb
Albibas, Amel
3de1249c-580c-42e3-9fde-ca82b40b0185
Behar, Ramnik
cae7deb5-66d5-4f1b-9b21-751a614345a3
Cho, Shin-Young
d78bd886-a2a3-4a92-b484-6e0b41aa268d
Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Theaker, Jeff
2e0133cc-197b-479a-9465-458e534deb63
Macleod, Amanda S.
306d3cbc-fbda-4f18-83eb-5c4defcd943a
French, Ruth
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd

Lai, Chester, August, Suzannah, Albibas, Amel, Behar, Ramnik, Cho, Shin-Young, Polak, Marta, Theaker, Jeff, Macleod, Amanda S., French, Ruth, Glennie, Martin, Al-Shamkhani, Aymen and Healy, Eugene (2016) OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential. Clinical Cancer Research, 1-42. (doi:10.1158/1078-0432.CCR-15-2614). (PMID:27034329)

Record type: Article

Abstract

Purpose: Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.
Experimental Design: Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. Results: FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (p<0.0001, n=86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4+ (p=0.005, n=10 tumors) and CD8+ T cells (p=0.043, n=9 tumors) and inhibited interferon-γ secretion by tumoral effector T cells (p=0.0186, n=11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (p<0.0001, n=15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4+ lymphocyte proliferation (p=0.0098, n=10 tumors). Tregs and OX40+ lymphocytes were more abundant in primary cSCCs which metastasized than in primary cSCCs which had not metastasized (n=48 and n=49 tumors respectively).
Conclusions: Tregs in cSCCs suppress effector T cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis.

Text
Clin Cancer Res-2016-Lai-1078-0432.CCR-15-2614.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 18 March 2016
e-pub ahead of print date: 31 March 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 390914
URI: https://eprints.soton.ac.uk/id/eprint/390914
ISSN: 1078-0432
PURE UUID: d88f0ebe-f124-406c-bbda-0b8851b81d24
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 07 Apr 2016 14:00
Last modified: 09 Dec 2019 19:41

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