Baseline tumor-infiltrating lymphocyte patterns and response to immune checkpoint inhibition in metastatic cutaneous melanoma

Isabella A J van Duin; Mark Schuiveling; Laurens S Ter Maat; Wouter A C van Amsterdam; Franchette van den Berkmortel; Marye Boers-Sonderen; Jan Willem B de Groot; Geke A P Hospers; Ellen Kapiteijn; Mariette Labots; Djura Piersma; Anne M R Schrader; Gerard Vreugdenhil; Hans Westgeest; Mitko Veta; Willeke A M Blokx; Paul J van Diest; Karijn P M Suijkerbuijk

doi:10.1016/j.ejca.2024.114190

Baseline tumor-infiltrating lymphocyte patterns and response to immune checkpoint inhibition in metastatic cutaneous melanoma

Eur J Cancer. 2024 Sep:208:114190. doi: 10.1016/j.ejca.2024.114190. Epub 2024 Jun 30.

Authors

Isabella A J van Duin¹, Mark Schuiveling², Laurens S Ter Maat³, Wouter A C van Amsterdam⁴, Franchette van den Berkmortel⁵, Marye Boers-Sonderen⁶, Jan Willem B de Groot⁷, Geke A P Hospers⁸, Ellen Kapiteijn⁹, Mariette Labots¹⁰, Djura Piersma¹¹, Anne M R Schrader¹², Gerard Vreugdenhil¹³, Hans Westgeest¹⁴, Mitko Veta¹⁵, Willeke A M Blokx¹⁶, Paul J van Diest¹⁶, Karijn P M Suijkerbuijk¹

Affiliations

¹ Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
² Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands. Electronic address: m.schuiveling@umcutrecht.nl.
³ Image Sciences Institute, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
⁴ Department of Data Science and Biostatistics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.
⁵ Department of Medical Oncology, Zuyderland Medical Center Sittard, Dr. H. van der Hoffplein 1, Sittard-Geleen 6162 BG, the Netherlands.
⁶ Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, the Netherlands.
⁷ Isala Oncology Center, Isala, Dokter van Heesweg 2, Zwolle 8025 AB, the Netherlands.
⁸ Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, the Netherlands.
⁹ Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333ZA, the Netherlands.
¹⁰ Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1118, Amsterdam 1081 Hz, the Netherlands.
¹¹ Department of Internal Medicine, Medisch Spectrum Twente, Koningsplein 1, Enschede 7512 KZ, the Netherlands.
¹² Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, the Netherlands.
¹³ Department of Internal Medicine, Maxima Medical Center, De Run 4600, Eindhoven 5504 DB, the Netherlands.
¹⁴ Department of Internal Medicine, Amphia Hospital, Molengracht 21, Breda 4818 CK, the Netherlands.
¹⁵ Medical Image Analysis, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
¹⁶ Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CG Utrecht, the Netherlands.

PMID: 38991284
DOI: 10.1016/j.ejca.2024.114190

Abstract

Introduction: The presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors.

Methods: In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors.

Results: Metastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07-1.28), increased PFS (HR 0.93, 95 % CI 0.87-0.996), and OS (HR 0.94, 95 % CI 0.89-0.99). When categorized, patients in the highest tertile TILs-WG score (15-100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores.

Conclusion: In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice.

Keywords: Immune checkpoint inhibition; Melanoma; Response; Tumor-infiltrating lymphocytes.

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Female
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Lymphocytes, Tumor-Infiltrating* / immunology
Male
Melanoma* / drug therapy
Melanoma* / immunology
Melanoma* / mortality
Melanoma* / pathology
Melanoma* / secondary
Melanoma, Cutaneous Malignant
Middle Aged
Progression-Free Survival
Retrospective Studies
Skin Neoplasms* / drug therapy
Skin Neoplasms* / immunology
Skin Neoplasms* / mortality
Skin Neoplasms* / pathology

Substances

Immune Checkpoint Inhibitors