867 Deciphering of radiotherapy-induced immunomodulation effect synergized with immunotherapy in hepatocellular carcinoma by spatial multi-omics profiling

• DOI: 10.1136/jitc-2022-sitc2022.0867
• Publication Date: 2022-11-08T01:11:16Z
• Authors: Mai Chan Lau; Lisda Suteja; Lawrence Cheung; Jeffrey Lim; Chun Jye Lim; Xinru Lim; Neslihan Kaya; Jiang Feng Ye; Felicia Wee; Han Chong Toh; Su Pin Choo; Suat Ying Lee; Joycelyn Jie Xin Lee; Jin Liu; Tony Kiat Hon Lim; Weiwei Zhai; David Tai; Joe Poh Sheng Yeong
• Keywords: 03 medical and health sciences; 0302 clinical medicine

<h3>Background</h3> Multiple clinical trials have shown an overall improved response rate in hepatocellular carcinoma (HCC) by combining radiotherapy (RT) with immunotherapy (IO), however, treatment rates remain low and unpredictable.¹ The suboptimal outcomes are largely due to the lack of knowledge underlying immunomodulation effect effective treatment-response biomarker. Previous studies using tissue-based assays like multiplexed immunofluorescence (mIF) demonstrated that cellular spatial organization within tumor microenvironment represents a critical factor influencing anti-tumor immunity.^{2, 3} Hence, we sought characterize in-situ molecular immune RT-treated HCC tissues, advance our understanding RT-induced its synergistic benefits IO. <h3>Methods</h3> Using cohort treated Yttrium-90 (Y90)-radioembolization (locoregional RT) anti-PD-1 combination therapy,¹ profiled FFPE tissues collected at baseline post-Y90 from 4 responders 8 non-responders NanoString9s Digital Spatial Profiler (DSP), 10× Genomics Visium technology, mIF. In DSP profiling, two types regions interest (ROIs) were selected pathologist: (1) geometric ROIs far Y90 beads, (2) contiguously micro-dissected contouring beads; data contains spatially barcoded spots (figure 1). <h3>Results</h3> Tumor Immune Dysfunction Exclusion (TIDE)⁴ analysis showed counter-intuitively decrease IO-responsiveness (i.e., higher TIDE scores) post-RT. revealed RT might induced systemic increase T-cell exclusion dysfunction non-responders, but opposite trends 2). A possibly CD274 (ligand PD-1) expression was seen (P _treatment &lt; 0.001, P _{distance-to-Y90-beads} = 0.04). Analysis higher-spatial-resolution cytotoxic abundance post-RT where cells spread over 3). mIF specific subset T-cells, CD38⁺CD8⁺, preferentially interacted _{cell-to-tumor distance} 0.08), <sub>cell-to-Y90-bead 0.001) 4). <h3>Conclusions</h3> TIDE, transcriptomic-based IO-biomarker mainly tested melanoma, is not directly applicable HCC. multi-omics enables identification RT-specific effects synergized IO HCC, including expression. To explain for T-cells further investigation on tumor-specificity cell-to-cell proximity needed. <h3>Trial Registration</h3> NCT03033446 <h3>References</h3> Tai D, Loke K, Gogna A, Kaya NA, Tan SH, Hennedige T, <i>et al</i>. Radioembolisation Y90-resin microspheres followed nivolumab advanced (CA 209–678): single arm, centre, phase 2 trial. <i>The Lancet Gastroenterology &amp; Hepatology</i>. 2021. doi: https://doi.org/10.1016/S2468-1253(21)00305-8. Barua S, Fang P, Sharma Fujimoto J, Wistuba I, Rao AUK, interaction regulatory T correlates survival non-small cell lung cancer. <i>Lung Cancer</i>. 2018;<b>117</b>:73–9. Epub 2018/02/08. 10.1016/j.lungcan.2018.01.022. PubMed PMID: 29409671; Central PMCID: PMCPMC6294443. Väyrynen JP, Haruki Lau MC, SA, Ugai Akimoto N, prognostic significance NK NKT-like via multimarker colorectal cancer microenvironment. <i>Cancer Immunol Res</i>. 2022;<b>10</b>(2):215–27. 2021/12/24. 10.1158/2326-6066.Cir-21-0772. 34937729; PMCPMC8816895. Jiang Gu Pan Fu Sahu Hu X, Signatures predict response. <i>Nature Medicine</i>. 2018;<b>24</b>(10):1550–8. 2018/08/22. 10.1038/s41591-018-0136-1. 30127393; PMCPMC6487502. <h3>Ethics Approval</h3> Singhealth CIRB 2016/2613