Abstract
BackgroundSmall cell lung cancer (SCLC) accounts for 10–15% of all lung malignancies and its prognosis is dismal. Although early studies have shown promising clinical activity of immune checkpoint blockers, the immune composition and expression of potentially actionable immunostimulatory targets in this malignancy are poorly understood.MethodsUsing multiplexed quantitative immunofluorescence (QIF), we measured the levels of 3 different B7 family ligands PD-L1, B7-H3, B7-H4 and major tumor infiltrating lymphocyte (TIL) subsets in 90 SCLC samples represented in tissue microarray format. Associations between the marker levels, clinicopathological variables and survival were studied.ResultsPD-L1 protein was detected in 7.3%, B7-H3 in 64.9% and B7-H4 in 2.6% of SCLC cases. The markers showed limited co-expression and were not associated with the level of TILs, age, gender and stage. Elevated B7-H4 was associated with shorter 5-year overall survival. The levels of CD3+, CD8+ and CD20+ TILs and the ratio of total/effector T-cells were significantly lower in SCLC than in non-small cell lung cancer. High levels of CD3+, but not CD8+ or CD20+ TILs were significantly associated with longer survival.ConclusionsTaken together, our study indicate variable expression and clinical role of B7-family ligands in SCLC with predominant expression of the candidate target B7-H3 and the presence of a limited cytotoxic anti-tumor immune response. These results support the evaluation of B7-H3 blockers and/or pro-inflammatory therapies in SCLC.
Highlights
Small cell lung cancer (SCLC) accounts for 10–15% of all lung malignancies and its prognosis is dismal
Multiplexed quantitative immunofluorescence (QIF) We measured the levels of PD-L1 (E1L3N, Cell Signaling technology), B7-H3 (D9M2L, Cell Signaling Technology), B7-H4 (D1M8I, Cell Signaling Technology), CD3, CD8, CD20 and pancytokeratin (AE1/AE3, DAKO) using QIF in Tissue microarray (TMA) slides containing the cohort cases
PD-L1, B7-H3 and B7-H4 were stained in serial sections from the TMA blocks using a previously described protocol with simultaneous detection of cytokeratin and 4′,6-diamidino-2-phenylindole (DAPI) [18, 19]
Summary
Small cell lung cancer (SCLC) accounts for 10–15% of all lung malignancies and its prognosis is dismal. Preliminary data from ongoing trials using antagonistic PD-1 and CTLA-4 antibodies in heavily pre-treated SCLCs suggests limited activity of monotherapy regimens, combination PD-1/CTLA-4 immune checkpoint blockade show encouraging results with objective responses in up to ~ 30% of cases [12, 13]. Despite these results, little is Carvajal-Hausdorf et al Journal for ImmunoTherapy of Cancer (2019) 7:65 known about the immune composition of SCLC and most studies characterizing immune cells or targets have used qualitative/subjective methods. Identification of dominant immune cell populations and/or expression of candidate immunotherapy targets in this tumor could support optimal design and interpretation of clinical trials
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