The role of HLA LOH in the development of Asian liver cancer

Immune evasion is one hallmark of cancer, whereby the immune system is unable to recognize and target tumors for destruction. Immunotherapy is a promising emerging treatment that has high potential to counteract immune evasion. However, its effectiveness is limited in liver cancer treatment due to lack of understanding of the mechanisms underlying immune evasion. Loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) may be important in the development of immune evasion, as HLA is crucial in neoantigen presentation for the effective initiation of an immune response. We characterized the effects of HLA LOH in liver cancer with regards to cytolytic activity, TCR diversity, as well as potential association with mutational signatures and its timing in tumor development. We found that tumors exhibiting HLA LOH were present in 66.7% of patients, and were associated with higher cytolytic activity, greater TCR diversity and aging mutational signatures. HLA LOH was found to occur mostly at the subclonal level. Hence, HLA LOH may have developed primarily in late stage tumors as an escape mechanism to circumvent a stronger anti-tumor immune response due to higher neoantigen burden. These findings may refine our understanding of immune resistance and have implications for future immunotherapeutic approaches.Bachelor of Science in Biological Science

The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer

Abstract AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL’s role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency

Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma

Background Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.Methods By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.Results We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.Conclusions This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC

Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities

Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy