OX40 and 4-1BB delineate distinct immune profiles in sarcoma
OX40 and 4-1BB delineate distinct immune profiles in sarcoma
Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.
CD137, TNFRSF9, TNFSFR4, agonist, immunotherapy
2066050
Melake, M.J.
334610c3-d21b-4f31-b1bf-553c48c55261
Smith, H.G.
ed60c787-c6ce-4ec7-9ed8-bfc13380e11f
Mansfield, D.
f2cafd0d-f82b-4b2c-9972-53f6472ccd24
Davies, E.
bc704d69-0e62-421c-abea-e1e1a7566439
Dillon, M.T.
55caf4d9-45a7-4bb8-8c59-cf12d998d0c7
Wilkins, A.C.
71b5c44a-cbbd-4a42-bdff-dd7775970561
Patin, E.C.
38d1bb1b-8e9a-41cb-b9c5-a5ade37c8bf8
Pedersen, M
55306140-2579-4e4b-8025-b08b508dbe9b
Buus, R.
d40ae407-f278-4b2b-9a51-82ba2f809ea4
Melcher, A.A.
e8655568-0594-4239-8661-b05900e49337
Thway, K.
9d48408a-6309-46a6-9b53-729cc6e0edeb
Miah, A.B.
ea9b1411-7829-4190-bf74-e779a3af6ac7
Zaidi, S.H.
52ccc64d-89e9-4d44-afb0-29a131204907
Hayes, A.J.
7aa9354f-0904-48dc-ae06-75340e6a56fd
Fenton, T.R.
087260ba-f6a1-405a-85df-099d05810a84
Harrington, K.J.
1078f503-d24f-40b0-a4ba-d5a5c0cff0bf
McLaughlin, M.
cef0d5b1-135d-411b-9276-af53dbf62ab1
9 May 2022
Melake, M.J.
334610c3-d21b-4f31-b1bf-553c48c55261
Smith, H.G.
ed60c787-c6ce-4ec7-9ed8-bfc13380e11f
Mansfield, D.
f2cafd0d-f82b-4b2c-9972-53f6472ccd24
Davies, E.
bc704d69-0e62-421c-abea-e1e1a7566439
Dillon, M.T.
55caf4d9-45a7-4bb8-8c59-cf12d998d0c7
Wilkins, A.C.
71b5c44a-cbbd-4a42-bdff-dd7775970561
Patin, E.C.
38d1bb1b-8e9a-41cb-b9c5-a5ade37c8bf8
Pedersen, M
55306140-2579-4e4b-8025-b08b508dbe9b
Buus, R.
d40ae407-f278-4b2b-9a51-82ba2f809ea4
Melcher, A.A.
e8655568-0594-4239-8661-b05900e49337
Thway, K.
9d48408a-6309-46a6-9b53-729cc6e0edeb
Miah, A.B.
ea9b1411-7829-4190-bf74-e779a3af6ac7
Zaidi, S.H.
52ccc64d-89e9-4d44-afb0-29a131204907
Hayes, A.J.
7aa9354f-0904-48dc-ae06-75340e6a56fd
Fenton, T.R.
087260ba-f6a1-405a-85df-099d05810a84
Harrington, K.J.
1078f503-d24f-40b0-a4ba-d5a5c0cff0bf
McLaughlin, M.
cef0d5b1-135d-411b-9276-af53dbf62ab1
Melake, M.J., Smith, H.G., Mansfield, D., Davies, E., Dillon, M.T., Wilkins, A.C., Patin, E.C., Pedersen, M, Buus, R., Melcher, A.A., Thway, K., Miah, A.B., Zaidi, S.H., Hayes, A.J., Fenton, T.R., Harrington, K.J. and McLaughlin, M.
(2022)
OX40 and 4-1BB delineate distinct immune profiles in sarcoma.
OncoImmunology, 11 (1), , [2066050].
(doi:10.1080/2162402X.2022.2066050).
Abstract
Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.
Text
OX40 and 4 1BB delineate distinct immune profiles in sarcoma
- Version of Record
More information
Accepted/In Press date: 31 March 2022
e-pub ahead of print date: 9 May 2022
Published date: 9 May 2022
Additional Information:
Funding Information:
This work was supported by Cancer Research UK; NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; Anthony Long Charitable Trust; Rosetrees Trust. This study was supported by RM/ICR NIHR Biomedical Research Centre, Rosetrees Trust, Cancer Research United Kingdom, and Anthony Long Charitable Trust. We would like to acknowledge and thank the Breast Cancer Now histopathology core facility.
Funding Information:
This study was supported by RM/ICR NIHR Biomedical Research Centre, Rosetrees Trust, Cancer Research United Kingdom, and Anthony Long Charitable Trust. We would like to acknowledge and thank the Breast Cancer Now histopathology core facility.
Publisher Copyright:
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
Keywords:
CD137, TNFRSF9, TNFSFR4, agonist, immunotherapy
Identifiers
Local EPrints ID: 472888
URI: http://eprints.soton.ac.uk/id/eprint/472888
ISSN: 2162-402X
PURE UUID: 5d16d6e9-3f3e-45cd-bf05-107e9617649d
Catalogue record
Date deposited: 05 Jan 2023 17:39
Last modified: 17 Mar 2024 04:11
Export record
Altmetrics
Contributors
Author:
M.J. Melake
Author:
H.G. Smith
Author:
D. Mansfield
Author:
E. Davies
Author:
M.T. Dillon
Author:
A.C. Wilkins
Author:
E.C. Patin
Author:
M Pedersen
Author:
R. Buus
Author:
A.A. Melcher
Author:
K. Thway
Author:
A.B. Miah
Author:
S.H. Zaidi
Author:
A.J. Hayes
Author:
K.J. Harrington
Author:
M. McLaughlin
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
