Universität zu Köln

Klein, Sebastian ORCID: 0000-0002-2188-9377, Mauch, Cornelia, Brinker, Klaus, Noh, Ka-Won, Knez, Sonja, Buettner, Reinhard, Quaas, Alexander and Helbig, Doris (2021). Tumor infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600(E/K) mutated malignant melanomas. Sci Rep, 11 (1). BERLIN: NATURE PORTFOLIO. ISSN 2045-2322

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Klein, Sebastian UNSPECIFIED orcid.org/0000-0002-2188-9377 UNSPECIFIED Mauch, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinker, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Noh, Ka-Won UNSPECIFIED UNSPECIFIED UNSPECIFIED Knez, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Helbig, Doris UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-571927
DOI:	10.1038/s41598-021-81330-4
Journal or Publication Title:	Sci Rep
Volume:	11
Number:	1
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDEPENDENT PREDICTOR; CELL Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57192