Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade

J Immunother Cancer. 2023 Dec 14;11(12):e007463. doi: 10.1136/jitc-2023-007463.


Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson's r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson's r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.

Keywords: biomarkers, tumor; carcinoma, basal cell; immunohistochemistry; pathology; tumor microenvironment.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • B7-H1 Antigen
  • Carcinoma, Basal Cell* / drug therapy
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Programmed Cell Death 1 Receptor
  • Skin Neoplasms* / drug therapy
  • Tumor Microenvironment


  • B7-H1 Antigen
  • Hepatitis A Virus Cellular Receptor 2
  • Programmed Cell Death 1 Receptor