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

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 (IHC) on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N=330 in the training and N= 3,992 in the validation set) linked to detailed clinico-pathological, biomarker and long term clinical outcome data. PD-1 and PD-L1 expression were also evaluated by IHC. 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 cutoffs 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 (BCSS) (HR: 0.71,95%CI 0.56-0.90), particularly among ER- 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 BCSS (HR: 0.49,95%CI 0.32-0.74).Conclusion: LAG-3+iTILs are enriched in ER- 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.

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