Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies

Oncoimmunology. 2023 Oct 4;12(1):2261248. doi: 10.1080/2162402X.2023.2261248. eCollection 2023.


Lymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 53 patients treated with combination anti-LAG-3 + anti-PD-1-based therapies. Eleven patients had received prior anti-PD-1-based treatment. Patients were categorized as responders (complete/partial response; n = 36) or non-responders (stable/progressive disease; n = 17) based on the Response Evaluation Criteria in Solid Tumours (RECIST). Tumor-infiltrating lymphocytes (TILs) were scored on hematoxylin and eosin-stained sections. LAG-3 expression was observed in 81% of patients, with staining in TILs and dendritic cells. Responders displayed significantly higher proportions of LAG-3+ cells compared to non-responders (P = .0210). LAG-3 expression positively correlated with TIL score (P < .01). There were no significant differences in LAG-3 expression between different sites of metastases (P > .05). Patients with ≥ 1% LAG-3+ cells in their tumors had significantly longer PFS compared to patients with < 1% LAG-3 expression (P = .0037). No significant difference was observed in overall survival between the two groups (P = .1417). Therefore, the assessment of LAG-3 expression via IHC warrants further evaluation to determine its role as a predictive marker of response and survival in metastatic melanoma.

Keywords: LAG-3; biomarker; immune checkpoint inhibitors; immunotherapy; melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor*
  • Humans
  • Immunohistochemistry
  • Immunotherapy
  • Melanoma* / drug therapy
  • Progression-Free Survival


  • Biomarkers, Tumor

Grants and funding

This work was supported by Melanoma Institute Australia, the New South Wales Department of Health, NSW Health Pathology, National Health and Medical Research Council of Australia (NHMRC) and Cancer Institute NSW. This research was funded by the Cancer Council NSW Program Grant (RG-15). T.N.G. is supported by a CINSW Early Career Fellowship (2020/ECF1244). G.V.L. and R.A.S. are supported by NHMRC Investigator Grants (GNT2007839 and GNT2018514). J.S.W. is supported by an NHMRC Fellowship (APP1174325). G.V.L. is supported by the Melanoma Foundation of the University of Sydney through the University of Sydney Medical Foundation. A.M.M. is supported by Nicholas and Helen Moore and Melanoma Institute Australia. E.C.P. was supported by the BB and A Miller Foundation’s Jani Haenke Melanoma Pathology Fellowship through Melanoma Institute Australia. I.P.d.S. is supported by a CINSW Early Career Fellowship. Project funding was supported by the Cancer Council NSW (RG19-15), Cancer Institute NSW (TPG2114) and Perpetual Philanthropic Services (2020HIG141).