Tumor-infiltrating lymphocytes and immune-related adverse events in advanced melanoma

Abstract

BackgroundThe predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development is unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pre-treatment primary and metastasis specimens and the subsequent development severe irAEs. MethodsWe retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-PD-1 +/- anti-CTLA-4 from ten hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (HE) stains of the primary melanoma and pre-treatment melanoma metastasis as “absent”, “non-brisk” or “brisk”. Univariable logistic regression was performed to assess the association between TIL scores and development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs. ResultsOf the 1346 eligible patients, 536 patients had primary melanoma specimens available, and 613 patients had metastasis specimens available. Severe irAEs occurred in 15% of anti-PD-1 treated patients and 49% of anti-PD-1 +anti-CTLA-4 treated patients.The presence of TILs was not associated with the occurrence of grade 3 or higher irAEs in primary melanoma specimens (p=0.70) nor pre-treatment metastasis specimens (p=0.91). In univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared to patients with absent TILs, for both primary specimen (Odds Ratio [OR] 1.15 [95% confidence interval [CI] 0.60-2.18]) and metastasis specimen (OR 0.77 [95% CI 0.37-1.59]. There was also no significant difference in the lifetime risk or timing of the development of severe irAEs in patients with TILs present compared to patients with TILs absent. ConclusionThere was no association between TIL score on H&E-stained slides from the primary melanoma or pre-treatment metastasis and the development of grade 3 or higher irAEs. Additionally, no correlation was found between the presence of TILs and the timing of irAEs.