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

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 of response. Methods In this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced cutaneous melanoma were identified. TILs were scored as absent, non-brisk or brisk on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases. Scoring systems evaluating the infiltration and intensity patterns (‘MIA-score’) and the percentage of stromal TILs were also evaluated. The primary outcome was objective response rate (ORR), with PFS and OS being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard regression analyses were performed, adjusting.for age, sex, disease stage, ICI type, BRAF mutation, lactate dehydrogenase (LDH) level and WHO performance score. Results Metastatic melanoma specimens were available for 650 patients and primary specimens from 565 patients.. No association was found between TILs in primary melanoma specimens and response. In metastatic specimens, patients with non-brisk TILs (aOR 1.56, 95% CI 1.06-2.29) and brisk TILs (aOR 3.28, 95% CI 1.72-6.56) had a higher probability of response, longer median PFS (9.2 and 19.4 vs. 6.5months [p=0.009]) and median OS (49.5 and 40.9 vs 21.3 months [p=0.007]) when compared to absent TILs. Similar results were noted using the MIA- and stromal TIL scores. Conclusion In advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases are associated with ICI response. This is independent of known clinical predictors. TILs are easily scored on readily available H&Es, which facilitates the use of this biomarker for ICI outcomes in clinical practice.