Expression of the Immune Checkpoints LAG-3 and PD-L1 in High-grade Serous Ovarian Carcinoma: Relationship to Tumor-associated Lymphocytes and Germline BRCA Status

Abstract

Ovarian high-grade serous carcinomas (HGSC) have shown lackluster responses to immunotherapies targeting the PD-1/PD-L1 axis, perhaps due to the coexistence of other mechanisms of immune evasion in this tumor type. Lymphocyte activation gene-3 (LAG-3) is another inhibitory immune checkpoint often expressed on tumor-associated lymphocytes which is targeted by drugs currently in clinical trials. Forty-eight HGSC with known germline BRCA mutation status were immunohistochemically stained for LAG-3, CD8, and FOXP3. Positive tumor-associated lymphocytes were enumerated and averaged over 10 high-power fields (HPF). PD-L1 immunostaining was also preformed and expression was evaluated on tumor cells and using the combined positive score (CPS). The average number of LAG-3-positve tumor-associated lymphocytes was 6/HPF (range: 0–25.6). Cytotoxic (CD8+) T cells averaged 30/HPF (range: 0–168.9), and regulatory (FOXP3) cells averaged 6.6/HPF (range: 0–76.3). Tumoral PD-L1 expression of ≥1% was observed in 27% (13/48) of cases, with only 8% (4/48) showing >5% staining; 81% (39/48) cases had a CPS ≥1. LAG-3-positive lymphocytes and PD-L1 expression were positively correlated, even after controlling for the overall level of CD8 and FOX3P+ lymphocyte infiltration. Germline BRCA status was not significantly associated with LAG-3, CD8, FOXP3, or PD-L1 expression. These findings indicate that immunotherapies targeting LAG-3 may benefit some ovarian HGSC patients, particularly when used in conjunction with anti-PD-1/PD-L1 approaches. The typically limited expression of LAG-3 and PD-L1 suggests that immunotherapeutic response may be muted in most HGSC even with a combination approach.

T‐cell activation is associated with high‐grade serous ovarian cancer survival

“…Many patients have no response to therapies that target CTLA‐4 and PD‐1 37 . Moreover, the lackluster response in clinic application of anti‐PD‐1 to HGSOC supports our result 38 . By genome‐wide gene expression correlation analysis, we found that PD‐1 expression was highly correlated with SIRPG, FASL, and CD8a.…”

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity

“…Like in breast cancer, there are also a few studies in ovarian cancer that do not support an association between BRCA -inactivation and immune cell infiltration. In an immunohistochemistry study including 48 patients with serous ovarian cancer and known germline BRCA mutation status (4 BRCA1 -mutated, 8 BRCA2 -mutated, 36 BRCA -wildtype), no association was found between germline BRCA mutation status and the infiltration of CD8 + T cells or Tregs or checkpoint expression (PD-L1 or LAG-3) [ 59 ]. Furthermore, analyses of transcriptome data of the TCGA yielded conflicting results [ 19 , 60 ].…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

“…BRCA1 regulates the cellular DNA damage response and repair, transcriptional regulation, and chromatin modeling, while BRCA2 plays a role in the DDR processes [ 9 , 19 , 23 , 53 , 56 , 92 , 163 ]. In PC, BRCA1 co-regulates the AR activity mediating tumor progression, while BRCA2 limits the metastatic potential of PC by MMP9 downregulation and inhibition of the PI3K/AKT and MAP/ERK pathways (which also regulate PD-L1 expression) [ 163 , 164 , 183 , 184 ].…”