Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Unresectable HB accounts for 8% of all pediatric LT. Post-LT relapse rates approach 20% indicating a need for more effective neoadjuvant chemotherapy.
*Methods: To discover novel targets, whole exome (WES), transcriptome and T-cell receptor (TCR) were sequenced and genome-wide methylation characterized in 16 HB, 14 removed at LT and 2 resected surgically.
*Results: The HB transcriptome was enriched for genes for IFN/T-cell signaling (JAK1, JAK2, STAT3, IFNAR1, IFNGR1), antigen presentation (HLA-A, β2M), b) T-cytotoxic cells (Tc, CD8A, CD8B). Immune response emerged as the top-ranked pathway (p=1.96E-07, Benjamini) based on differentially methylated promoters of IFN-responsive (e.g. IFNA13) chemokine (e.g. CCR5), immune checkpoint (IC such as BTLA, CD86) and antigen presentating (e.g, HLADQB2) genes. TCRβ clonality and frequency was correlated with mRNA signatures for Tc (Spearman r=0.4 and 0.47, respectively). Non synonymous single nucleotide variants predicted MHC-class-I-binding tumor-specific neoantigens (TSA) in seven of 15 (45%) tumors with somatic and germline WES. Up to three 9-mer TSA peptides were synthesized for 5 of 7 tumors predicted to harbor TSA. Three of these 5 tumors relapsed after LT. Two of 3 relapses were fatal. Pooled peptides were used to stimulate peripheral blood leukocytes (PBL) from healthy adults with corresponding cognate MHC class I alleles (self-like) and non-cognate (non-self) PBL. Frequencies of CD154+T-memory cells (TcM) rose from background of <0.1%, to 1.7+/-0.7% with TSA stimulation, and further to 7.3+/-5.2% with anti-PD-L1 added to TSA (n=4). Non-self PBL were non-reactive. Single cell RNA- and TCR sequencing of CD45+tumor infiltrating leukocytes (TILs) and CD45- tumor cells showed lower CD45+ : CD45- ratio (1 vs 1.4) and lower frequencies of NK cells (1% vs 4%) and HLA-DR+ (B-cells, dendritic cells and monocytes) antigen presenting cell (21% vs 40.5%) in the tumor which led to fatal relapse compared with mean frequencies in two tumors cured with resection, respectively. Relative frequencies of CD8A+TILs expressing genes for ICs were similar to or numerically lower compared with those among CD45- tumor cells (PDL 0.65 vs 0.52, PD-L1 0.04 vs 0.11, TIGIT 0.96 vs 1.2, CTLA4 0.4 vs 0.54, TIM3 0.83 vs 2.47, BTLA 0.15 vs 0.28, LAG3 1.47 vs 1.47). The Inverse Simpson Index of the clonotype frequencies showed fewer TCR clonotypes in the tumor which relapsed and harbored six TSAs (index 918) compared with the remaining two tumors (indices 1133 and 2316, respectively) who remain disease-free after resection.
*Conclusions: Nearly 40% of unresectable HB requiring LT, including most relapse-prone HB, appear to be immunogenic. Adjunctive immune checkpoint inhibitor therapy can potentially reduce post-transplant relapse.
To cite this abstract in AMA style:Ningappa M, Ashokkumar C, Garifallou J, Gonzalez M, Hakonarson H, Ranganathan S, Higgs BW, Sindhi R. Relapse-Prone Unresectable Hepatoblastoma (HB) Requiring Liver Transplantation (LT) Are Immunogenic and May Be Sensitive to Immune Checkpoint Inhibitors [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/relapse-prone-unresectable-hepatoblastoma-hb-requiring-liver-transplantation-lt-are-immunogenic-and-may-be-sensitive-to-immune-checkpoint-inhibitors/. Accessed August 5, 2021.
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