Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas

Abstract Patients with metastasized malignant melanomas (MM) are regularly treated with immune checkpoint inhibitors (CPI). Within our study, we evaluated the predictive value of tumor infiltrating lymphocyte (TIL) clusters in primary MM and its association to molecular subtypes to predict response...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sebastian Klein, Cornelia Mauch, Klaus Brinker, Ka-Won Noh, Sonja Knez, Reinhard Büttner, Alexander Quaas, Doris Helbig
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3199c96a9b2944c8a2c270cc0d8bd80c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3199c96a9b2944c8a2c270cc0d8bd80c
record_format	dspace
spelling	oai:doaj.org-article:3199c96a9b2944c8a2c270cc0d8bd80c2021-12-02T13:48:41ZTumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas10.1038/s41598-021-81330-42045-2322https://doaj.org/article/3199c96a9b2944c8a2c270cc0d8bd80c2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81330-4https://doaj.org/toc/2045-2322Abstract Patients with metastasized malignant melanomas (MM) are regularly treated with immune checkpoint inhibitors (CPI). Within our study, we evaluated the predictive value of tumor infiltrating lymphocyte (TIL) clusters in primary MM and its association to molecular subtypes to predict response to CPI treatment. A cohort of 90 MM patients who received CPI treatment were collected from a single center, as well as a validation cohort of 351 patients from the TCGA database (SKCM) who received standard of care. A deep-convolutional-neural network (U-Net) was trained to detect viable tumor areas on H&E whole-slide-images, following a quantitative detection of TILs with help of a separate additional neural network. The number of TIL clusters was associated with response to CPI in 90 MM patients (AUC = 0.6), even more pronounced within the sub-cohort of BRAF V600 E/K -mutated MM patients (AUC = 0.7, n = 32). Interestingly, the TIL clusters in NRAS-mutated as well as wildtype MM (BRAF-wt, NRAS-wt) tumors, did not demonstrate a predictive value of CPI response (AUC = 0.5, n = 25). Moreover, PD-L1 expression had a limited predictive value within our cohort. In parallel, within an independent cohort of MM patients (TCGA, n = 351), the number of TIL clusters was associated with improved survival in BRAF V600 E/K mutated MM (p < 0.0001, n = 164) but neither in NRAS-mutated (55.7 months vs. 63.0 months, respectively, p = 0.590, n = 85) nor BRAF/NRAS-wildtype MM patients (52.4 months vs. 47.4 months, respectively, p = 0.581, n = 104). While TILs in MM have been associated with improved survival, we show—for the first time—that TIL clusters are associated with response to immunotherapy in BRAF V600 E/K mutated MM.Sebastian KleinCornelia MauchKlaus BrinkerKa-Won NohSonja KnezReinhard BüttnerAlexander QuaasDoris HelbigNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sebastian Klein Cornelia Mauch Klaus Brinker Ka-Won Noh Sonja Knez Reinhard Büttner Alexander Quaas Doris Helbig Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
description	Abstract Patients with metastasized malignant melanomas (MM) are regularly treated with immune checkpoint inhibitors (CPI). Within our study, we evaluated the predictive value of tumor infiltrating lymphocyte (TIL) clusters in primary MM and its association to molecular subtypes to predict response to CPI treatment. A cohort of 90 MM patients who received CPI treatment were collected from a single center, as well as a validation cohort of 351 patients from the TCGA database (SKCM) who received standard of care. A deep-convolutional-neural network (U-Net) was trained to detect viable tumor areas on H&E whole-slide-images, following a quantitative detection of TILs with help of a separate additional neural network. The number of TIL clusters was associated with response to CPI in 90 MM patients (AUC = 0.6), even more pronounced within the sub-cohort of BRAF V600 E/K -mutated MM patients (AUC = 0.7, n = 32). Interestingly, the TIL clusters in NRAS-mutated as well as wildtype MM (BRAF-wt, NRAS-wt) tumors, did not demonstrate a predictive value of CPI response (AUC = 0.5, n = 25). Moreover, PD-L1 expression had a limited predictive value within our cohort. In parallel, within an independent cohort of MM patients (TCGA, n = 351), the number of TIL clusters was associated with improved survival in BRAF V600 E/K mutated MM (p < 0.0001, n = 164) but neither in NRAS-mutated (55.7 months vs. 63.0 months, respectively, p = 0.590, n = 85) nor BRAF/NRAS-wildtype MM patients (52.4 months vs. 47.4 months, respectively, p = 0.581, n = 104). While TILs in MM have been associated with improved survival, we show—for the first time—that TIL clusters are associated with response to immunotherapy in BRAF V600 E/K mutated MM.
format	article
author	Sebastian Klein Cornelia Mauch Klaus Brinker Ka-Won Noh Sonja Knez Reinhard Büttner Alexander Quaas Doris Helbig
author_facet	Sebastian Klein Cornelia Mauch Klaus Brinker Ka-Won Noh Sonja Knez Reinhard Büttner Alexander Quaas Doris Helbig
author_sort	Sebastian Klein
title	Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
title_short	Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
title_full	Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
title_fullStr	Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
title_full_unstemmed	Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas
title_sort	tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in braf v600 e/k mutated malignant melanomas
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3199c96a9b2944c8a2c270cc0d8bd80c
work_keys_str_mv	AT sebastianklein tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT corneliamauch tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT klausbrinker tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT kawonnoh tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT sonjaknez tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT reinhardbuttner tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT alexanderquaas tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas AT dorishelbig tumorinfiltratinglymphocyteclustersareassociatedwithresponsetoimmunecheckpointinhibitioninbrafv600ekmutatedmalignantmelanomas
_version_	1718392429691797504

Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600 E/K mutated malignant melanomas

Ejemplares similares