Abstract A04: Analysis of molecular and immune features that correlate with serum lactate dehydrogenase (LDH) levels in patients (pts) with metastatic melanoma
Authors: Fernando Cintra Lopes Carapet, Grant Fischer, Aron Joon, Huiqin Chen, Lauren Haydu, Sandra Lee, Melissa Saul, Savi Appana, John Thompson, Graham Mann, Jennifer McQuade, Alexander Lazar, Michael Tetzlaff, John Kirkwood, Richard Scolyer, Georgina Long, Michael Davies
Journal: Cancer Research (2020)

Abstract Background: Elevated serum LDH is a poor prognostic factor in pts with MM. It is currently unknown if serum LDH levels correlate with molecular or immune differences in tumors, including LDH expression. We analyzed resected melanoma metastases to identify features that correlate with serum LDH elevation. Methods: Metastases with serum LDH levels measured within 30 days of surgery were included in the study: (1) a TMA of resected stage IV metastases from MD Anderson (MDACC) (n=207); (2) resected stage IV metastases from MDACC with previously acquired RNA-sequencing (RNA-seq) and CD8+ immunohistochemistry (IHC) data (n=24); (3) publicly available data for regional metastases from the melanoma TCGA (n=104) from MDACC and the Melanoma Institute of Australia. IHC was performed for LDHA, LDHB, PTEN, PD-L1, MITF, and Ki67 on the stage IV TMA, and publicly available data for DNA, RNA, and proteins for the TCGA samples were downloaded. Data were analyzed to identify features that differed between tumors with elevated and normal serum LDH levels. TCGA and stage IV tumors expressing the 25% highest and lowest LDHA and LDHB by RNA-seq were also compared. Results: IHC of the stage IV TMA identified no significant associations with serum LDH levels, including tumor LDHA (p=0.69) and LDHB (p=0.93) expression. Serum LDH was elevated in 33.3% of stage IV metastases with RNA-seq data and 21.6 % of TCGA regional metastases, which by Ensemble of Gene Set Enrichment Analyses (EGSEA) correlated with decreased expression of interferon alpha (q=8.26 × 10−14 and q=2.31 × 10−14), interferon gamma (q=9.46 × 10−14 and q=2.34 × 10−19), and inflammatory response (q= 1.26 × 10−20 and q=4.17 × 10−28) gene sets. Fewer (p=0.0464) CD8+ T cells were detected in stage IV tumors from pts with elevated serum LDH. Comparison of stage IV and TCGA tumors with high vs. low LDHA and LDHB mRNA expression levels did not correlate with serum LDH status, but significant enrichment of oxidative phosphorylation (q=6.32 × 10−21 and q=5.69 × 10−19), pyruvate metabolism (q= 7.90 × 10−16 and q=1.78 × 10−14), and citrate cycle (q= 1.51 × 10−06 and q=5.44 × 10−06) gene sets were detected in LDHA-high tumors. Increased LDHB expression correlated with enrichment of citrate cycle (q= 4.04 × 10−16 and q= 1.68 × 10−14), pyruvate metabolism (q= 2.34 × 10−11 and q=1.50 × 10−10), and glycolysis (q= 2.92 × 10−9 and q=1.55 × 10−8) gene sets. Conclusions: Elevated serum LDH levels correlated with decreased expression of immune response genes, but not LDHA or LDHB expression, in melanoma regional and distant metastases. Elevated serum LDH also correlated with decreased CD8+ T cell infiltrates by IHC. LDHA and LDHB expression levels in regional metastases correlated with distinct metabolic pathways, but not serum LDH levels. Citation Format: Fernando Cintra Lopes Carapet, Grant Fischer, Aron Joon, Huiqin Chen, Lauren Haydu, Sandra Lee, Melissa Saul, Savi Appana, John Thompson, Graham Mann, Jennifer McQuade, Alexander Lazar, Michael Tetzlaff, John Kirkwood, Richard Scolyer, Georgina Long, Michael Davies. Analysis of molecular and immune features that correlate with serum lactate dehydrogenase (LDH) levels in patients (pts) with metastatic melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A04.