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

## TL;DR

This study found no link between tumor-infiltrating lymphocytes and severe immune-related side effects in melanoma patients treated with immunotherapy.

## Contribution

The study is the first to show no association between TILs in melanoma and immune-related adverse events in a large patient cohort.

## Key findings

- TILs in primary and metastatic melanoma were not linked to severe immune-related adverse events.
- No correlation was found between TIL presence and the timing of immune-related adverse events.
- Patients with brisk TILs had similar odds of developing severe adverse events as those with absent TILs.

## Abstract

The predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development remains unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pretreatment primary and metastasis specimens and the subsequent development of severe irAEs.

We retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-programmed cell death protein 1 (PD-1) with or without anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) from 10 hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (H&E) stains of the primary melanoma and pretreatment melanoma metastasis as ‘absent’, ‘nonbrisk’, or ‘brisk’. A univariable logistic regression analysis was carried out to assess the association between the TIL scores and the development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs.

Of 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 irAEs in primary melanoma specimens (P = 0.70) nor pretreatment metastasis specimens (P = 0.91). In the univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared with patients with absent TILs, for both primary specimen (odds ratio 1.15, 95% confidence interval 0.60-2.18) and metastasis specimen (odds ratio 0.77, 95% confidence interval 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 with patients with TILs absent.

There was no association between the TIL scores on H&E-stained slides from the primary melanoma or pretreatment 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.

•Examining the role of TILs in severe irAE development in immune checkpoint inhibitor treated patients.•Five hundred and thirty-six patients had primary melanoma specimens, and 613 patients had pretreatment metastasis specimens available.•TILs were scored on H&E-stained slides as ‘absent’, ‘nonbrisk’, or ‘brisk’ in primary melanoma and metastasis specimens.•No significant association was found between TIL abundance and the occurrence of grade ≥3 irAEs.•The presence of TILs did not correlate with the development or timing of severe irAEs.

Examining the role of TILs in severe irAE development in immune checkpoint inhibitor treated patients.

Five hundred and thirty-six patients had primary melanoma specimens, and 613 patients had pretreatment metastasis specimens available.

TILs were scored on H&E-stained slides as ‘absent’, ‘nonbrisk’, or ‘brisk’ in primary melanoma and metastasis specimens.

No significant association was found between TIL abundance and the occurrence of grade ≥3 irAEs.

The presence of TILs did not correlate with the development or timing of severe irAEs.