579 Lactate dehydrogenase C-associated molecular networks predict enhanced tumor growth and impaired immune response in breast cancer. (9th November 2020)

• Record Type: Journal Article
• Authors: Decock, Julie; Jana, Adviti
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A347
• Page End: A347
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0579
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Cancer testis antigens (CTAs) have gained interest in the field of anti-cancer therapy as they offer the opportunity to target tumor cells with little off/on-target side effects given their restricted expression patterns. Several CTAs have been implicated as mediators of cancer hallmarks including cancer metabolism, proliferation, survival, and cell motility. Lactate dehydrogenase C (LDHC) expression has been observed in various cancer types and likely confers a survival advantage to tumor cells through metabolic reprograming. Thus, targeting LDHC has the potential to inhibit tumor growth and release the anti-tumor immune response from the acidic immunosuppressive microenvironment. This study aimed to explore the changes in the transcriptome of breast cancer cells upon in vitro LDHC targeting. Methods: We silenced LDHC expression in two breast cancer cell lines (BT549, HCC1954) and investigated the downstream effects on the tumor cell transcriptome. In addition, differentially expressed genes were subjected to regulatory network analyses and expression of key regulators was interrogated in the TCGA breast cancer dataset. Results: We identified 47 up- and 55 down-regulated transcripts after LDHC silencing (2.0-fold change, adj p<0.05). Specifically, we found that LDHC expressing breast cancer cells display an enrichment of genes involved in canonical pathways regulating cell cycle checkpoint control, BRCA1-mediated DNA damage response and NF-kb signaling in response to infection, which is in line with some of our unpublished work. In support, downstream effector analysis demonstrate that LDHC silencing negatively affects biological functions such as cellular development, cellular growth and proliferation, cell migration and cell infiltration. Upstream regulator analyses revealed that the observed changes in gene expression are associated with mTOR (p=1.27e-5, z=2.242) and CASP3 (p=3.2e-4, z=2.250) mechanistic networks, which in the presence of LDHC are predicted to activate TP53, Myc, NF-KB complex, STAT1/3, PRKC, CDK2, FOXO3 and HIF-1a while inhibiting SMAD3, PTEN, ATM, IL18 and BCL2. Furthermore, causal network analysis revealed a higher-level regulation by miR378a-3p (p=1.4e-7, z=-3.117), affecting the mechanistic networks and ultimately promoting tumor cell viability and proliferation, tumor cell movement and cell cycle progression in LDHC expressing cells. Interestingly, the miR378a causal network also indicated inhibition of the immune response in LDHC positive cells. Correlation analysis using the TCGA breast cancer dataset indicated a weak correlation between LDHC expression and the mechanistic regulator mTOR (R=0.26, p=1.82e-18). Conclusions: Our findings demonstrate that therapeutic targeting of LDHC may inhibit tumor growth while releasing the anti-tumor immune response in breast cancer, and warrant further in-depth investigation. Acknowledgements: This work was supported by a grant from the Qatar Biomedical Research Institute (grant number VR94), awarded to Dr Julie Decock.