Classification of the tumor immune microenvironment and associations with outcomes in patients with metastatic melanoma treated with immunotherapies

J Immunother Cancer. 2023 Oct;11(10):e007144. doi: 10.1136/jitc-2023-007144.


Background: Tumor microenvironment (TME) characteristics are potential biomarkers of response to immune checkpoint inhibitors in metastatic melanoma. This study developed a method to perform unsupervised classification of TME of metastatic melanoma.

Methods: We used multiplex immunohistochemical and quantitative pathology-derived assessment of immune cell compositions of intratumoral and peritumoral regions of metastatic melanoma baseline biopsies to classify TME in relation to response to anti-programmed cell death protein 1 (PD-1) monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 (ipilimumab (IPI)+PD-1).

Results: Spatial profiling of CD8+T cells, macrophages, and melanoma cells, as well as phenotypic PD-1 receptor ligand (PD-L1) and CD16 proportions, were used to identify and classify patients into one of three mutually exclusive TME classes: immune-scarce, immune-intermediate, and immune-rich tumors. Patients with immune-rich tumors were characterized by a lower proportion of melanoma cells and higher proportions of immune cells, including higher PD-L1 expression. These patients had higher response rates and longer progression-free survival (PFS) than those with immune-intermediate and immune-scarce tumors. At a median follow-up of 18 months (95% CI: 6.7 to 49 months), the 1-year PFS was 76% (95% CI: 64% to 90%) for patients with an immune-rich tumor, 56% (95% CI: 44% to 72%) for those with an immune-intermediate tumor, and 33% (95% CI: 23% to 47%) for patients with an immune-scarce tumor. A higher response rate was observed in patients with an immune-scarce or immune-intermediate tumor when treated with IPI+PD-1 compared with those treated with PD-1 alone.

Conclusions: Our study provides an automatic TME classification method that may predict the clinical efficacy of immunotherapy for patients with metastatic melanoma.

Keywords: Immunotherapy; Melanoma; PATHOLOGY; Tumor Microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen*
  • Humans
  • Immunotherapy / methods
  • Ipilimumab / therapeutic use
  • Melanoma* / drug therapy
  • Programmed Cell Death 1 Receptor
  • Tumor Microenvironment


  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Ipilimumab