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Updated: Aug 4, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Lymphocyte-activating gene 3 expression in tumor cells predicts immune checkpoint inhibitor response in triple
Ji-Yeon Kim1,2, Jeehyun Kim3, Eun Yoon Cho3
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Introduction:
Immune checkpoint inhibitor (ICI) is one of the standard treatment strategies in triple negative breast cancer (TNBC). However, the benefit of ICI with chemotherapy is limited in metastatic TNBC. In this study, we evaluated the effect of PD-L1 and LAG-3 expression on tissue microenvironment of mTNBC treated with ICI.
Methods:
We reviewed representative formalin-fixed paraffin embedded specimens from metastatic or archival tumor tissues of TNBCs who treated with PD-1/PD-L1 inhibitors in metastatic setting. We used the Opal multiplex Detection kit with six antibodies (anti-PD-L1, anti-LAG-3, anti-CD68, anti-panCK, anti-CD8, anti-CD107a/LAMP antibody).
Results:
We evaluated the association between LAG-3+cells and survival outcome regarding CK expression. Stromal LAG-3+/CK+ and LAG-3+/CK- cells were not associated with ICI-progression free survival(PFS) (P=0.16). However, LAG-3+ cell distributions in the tumor area impacted on ICI-PFS. A high density of LAG-3+CK+ cells was associated with shorter ICI-PFS compared with low densities of both LAG-3+CK+ and LAG-3+CK- cells (1.9 vs. 3.5 months). In addition, a high density of LAG-3+CK- cells had a relatively longer ICI-PFS compared with other groups (P=0.01). In terms of total area, the pattern of densities of LAG-3+CK+ cells and LAG-3+CK- cells were similar to those in the tumor area In addition, ICI-PFS of LAG-3+CK- and LAG-3+CK+ cell densities in the total area was equal to that in the tumor area.
Discussion:
In conclusion, our findings revealed tumor-intrinsic LAG-3 expression was the resistance mechanism toward PD-1/PD-L1 inhibitors in mTNBCs. Multivariate analysis also suggested that LAG-3 expression in tumor cells was an independent predictive biomarker.
Insights
Immune checkpoint inhibitors (ICI) show limited benefit in metastatic triple-negative breast cancer (TNBC). Tumor-intrinsic LAG-3 expression acts as a resistance mechanism to ICI therapy, suggesting it as a predictive biomarker.
Area of Science:
- Oncology
- Immunotherapy
- Breast Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) are standard treatments for triple-negative breast cancer (TNBC).
- The efficacy of ICIs combined with chemotherapy is restricted in metastatic TNBC (mTNBC).
- Understanding resistance mechanisms is crucial for improving ICI therapy outcomes.
Purpose of the Study:
- To investigate the role of PD-L1 and LAG-3 expression in the tumor microenvironment of mTNBC treated with ICIs.
- To evaluate the association between LAG-3 expression and survival outcomes in mTNBC patients receiving ICI therapy.
Main Methods:
- Analysis of formalin-fixed paraffin-embedded tumor specimens from mTNBC patients treated with PD-1/PD-L1 inhibitors.
- Utilized Opal multiplex detection with antibodies for PD-L1, LAG-3, CD68, panCK, CD8, and CD107a/LAMP.
- Assessed the correlation between LAG-3-positive cell density and progression-free survival (PFS).
Main Results:
- Stromal LAG-3 expression (both LAG-3+/CK+ and LAG-3+/CK-) did not significantly correlate with ICI-PFS.
- LAG-3+ cell distribution within the tumor area significantly impacted ICI-PFS.
- High densities of LAG-3+CK+ cells were associated with shorter ICI-PFS, while high densities of LAG-3+CK- cells showed a trend towards longer ICI-PFS.
Conclusions:
- Tumor-intrinsic LAG-3 expression represents a resistance mechanism to PD-1/PD-L1 inhibitors in mTNBC.
- LAG-3 expression in tumor cells is a potential independent predictive biomarker for ICI therapy response in mTNBC.
