Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases.

Background: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma.
Methods: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy.
Findings: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival.
Interpretation: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy.
Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
Competing Interests: Declaration of interests SF received personal fees from Kyowa Kirin and Takeda Pharmaceuticals, institutional grants from NeraCare, SkylineDx, and BioNTech, all outside the submitted work. TA reports institutional grants and personal fees from Novartis, institutional grants from NeraCare, Sanofi, SkylineDx, personal fees from CeCaVa, Pierre Fabre, BMS all outside the submitted work, participate on a data safety monitoring board for Unicancer. DLR reports grants and personal fees from Amgen, Astra Zeneca, Cepheid, Konica—Minolta, Lilly, NextCure personal fees from Cell Signaling Technology, Danaher, Fluidigm, GSK, Merck, Monopteros, NanoString, Odonate, Paige. AI, Regeneron, Roche, Sanofi, Ventana and Verily, royalties from Rarecyte, all outside the submitted work. CG reports grants and personal fees from NeraCare, Novartis, Roche, Sanofi, personal fees from Amgen, BMS, MSD, and Philogen, all outside the submitted work. TE reports personal fees from Novartis, BMS, Almirall Hermal, CureVac, Sanofi, MSD, Pierre Fabre and institutional grants from MSD, Sanofi, BMS, Pfizer, GenenTech, Seagan, Regeneron all outside the submitted work. IB reports having received speaker fees from Bayer, Pfizer, Takeda and AstraZeneca. MR reports grants from AB Science, Abbott, AbbVie, Alcedis, Almirall Hermal, Amgen, Anaptys Bio, Argenx, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CureVac, DelArrivo, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Dynavax Tech, Eli Lilly, Galderma, Genentech, GSK, Hoffmann La Roche, Hokusai, Idera Pharmaceuticals, Ilkos Therapeutic, Immatics biotechnologies, Incyte, Iovance Biotherapeutics, Janssen Cilag, Johnson & Johnson, LEO Pharma, Merck, MSD Sharp &Dohme, Novartis Pharmaceuticals, PellePharm, Pfizer, Philogen, Regeneron Pharmaceuticals, Sanofi Aventis, Schering Plough, Sun Pharma, Technische Universitat Dresden, Topaz Therapeutics, UCB, Universitatsklinik Essen, Universitatklinik Koln, Wilhelm Sander-Stiftung, 4SC. The other authors report no potential conflicts of interest.
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