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Ann Oncol. 2017 Dec 1;28(12):2977-2984. doi: 10.1093/annonc/mdx557.

LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors.

Author information

1
Genetic Pathology Evaluation Centre.
2
Pathology and Laboratory Medicine Department, University of British Columbia, Vancouver.
3
British Columbia Cancer Agency, Vancouver, Canada.

Abstract

Background:

Novel immune checkpoint blockade strategies are being evaluated in clinical trials and include targeting the lymphocyte activation gene 3 (LAG-3) checkpoint, alone or in combination with PD-1/PD-L1 blockade. We investigated LAG-3 expression and its prognostic value in a large series of breast cancer patients, and correlated LAG-3 expression with key biomarkers including PD-1 and PD-L1.

Experimental design:

LAG-3 expression was evaluated by immunohistochemistry on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N = 330 in the training and N= 3992 in the validation set) linked to detailed clinicopathologic, biomarker and long-term clinical outcome data. PD-1 and PD-L1 expressions were also evaluated by immunohistochemistry. Stromal or intra-epithelial tumor infiltrating lymphocytes (sTILs or iTILs) expressing LAG-3 or PD-1 were assessed by absolute count. PD-L1 expression was evaluated as the percentage of positive carcinoma cells per core. Kaplan-Meier curves and Cox proportional hazard models were used for survival analyses.

Results:

After locking down interpretation cut-offs on the training set, LAG-3+ iTILs were found in 11% of cases in the validation set. In both sets, LAG-3+ iTILs were significantly associated with negative prognostic factors: young age, large tumor size, high proliferation, HER2E and basal-like breast cancer subtypes. In multivariate analyses, breast cancer patients with LAG-3+ iTILs had a significantly improved breast cancer-specific survival [hazard ratio (HR): 0.71, 95% CI 0.56-0.90], particularly among estrogen receptor-negative patients (HR: 0.50, 95% CI 0.36-0.69). Furthermore, we found that 53% of PD-L1+ and 61% of PD-1+ cases were also positive for LAG-3+ iTILs. Concurrent infiltration of LAG-3+ and CD8+ iTILs was significantly associated with increased breast cancer-specific survival (HR: 0.49, 95% CI 0.32-0.74).

Conclusion:

LAG-3+ iTILs are enriched in estrogen receptor-negative breast cancers and represent an independent favorable prognostic factor. In addition, a high proportion of PD-1/PD-L1+ tumors are co-infiltrated with LAG-3+ TILs, supporting potential immune checkpoint blockade combination strategies as a treatment option for breast cancer patients.

KEYWORDS:

LAG-3; breast cancer; immune checkpoints; immuno-oncology; immunohistochemistry

PMID:
29045526
DOI:
10.1093/annonc/mdx557
[Indexed for MEDLINE]

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