{"doi":"10.1002/cac2.12620","title":"Acquired RD3 loss regulates immune surveillance in high‐risk and therapy defying progressive neuroblastoma","abstract":"Neuroblastoma (NB) is the most common extra cranial solid tumor in children and comprises one tenth of all childhood cancer deaths. More than half of infants presented with NB, a designated “cold tumor” with low immune cell repertoire in the tumor microenvironment (TME) [1], develop progressive disease (PD). The low numbers of tumor infiltrating lymphocytes (TILs) and the limited anti-tumorigenic potential; low expression of major histocompatibility complex (MHC) class I molecules; limitations in the tumor suppressive immune cell infiltration in TME; and the presence of immune-suppressive cytokines are the critical reasons for poor prognosis (< 10% long term overall survival [OS]) in high-risk NB that contributes to about 10% of all childhood cancer deaths [2]. Immune cell components of both the innate and adaptive immune response recognize tumor specific antigens expressed on neoplastic cells and promote an immune response to eliminate cancer cells and to develop immune memory to prevent recurrence [2, 3]. However, these protective responses can take an impromptu turn in favor of tumor progression in immune-compromised individuals, and those tumors with lower immunogenicity [4]. This establishes cancer immune editing within the TME leading to acquired tumor immune evasion (TIME) that substantially contributes to cancer evolution and poor outcomes [2, 4, 5]. Hence, it is of great interest to unearth the drivers and the mechanisms that coordinate TIME, so as to develop effective therapeutic strategies for high-risk and for therapy defying progressive tumors. Our recent studies sequentially identified the availability and abundance of Retinal Degeneration protein 3 (RD3) in human adult and fetal tissues beyond retina [6, 7]; de novo loss of RD3 expression under therapy pressure; its predictive/prognostic relevance to NB clinical outcomes and; defined its novel NB evolution stabilization function [8, 9]. Assessing the function of RD3 in NB TIME (Figure 1), here we recognized the unique requirement for RD3 to maintain NB immune surveillance. The immune microenvironment enclosed within the TME plays a discrete role in tumor immune surveillance. CIBERSORTx analysis (P < 0.05) employing “gene surrogate strategy” in whole genome RNA sequencing (RNA-seq) profiles from our bed-to-bench study identified 22 immune cell-types in NB-TME (Supplementary Figure S1). Differential gene expression analysis within CIBERSORTx [10] in RD3 reverse engineered (RD3-knockout) three unique models inflicted a “model-dependent” loss (vs. RD3+) of naïve B cells, CD8-cells, naïve and memory resting CD4-T cells, follicular as well γδ T-cells, resting and activated natural killer (NK) cells, M0, M1, and M2 macrophages, resting and activated mast cells, eosinophils and, a “model-independent” loss (vs. RD3+) of neutrophils (Supplementary Figure S2A). The decreased infiltration of these crucial immune cells that normally protect against tumor initiation and development suggests that RD3 negatively regulates TIME within the NB-TME. Identifying the mechanism(s) how RD3 regulates TIME in NB, the effector role of RD3, if any, on the 532 immune-related transcripts (42 of 574 CIBERSORTx identified relevant transcripts were excluded for their low copy number in sequencing) were investigated. Log2 fold-change coupled with False Discovery Rate (FDR) computed from RNA-seq in three exclusive models identified a RD3-dependent, “model-independent” 27-gene signature (Supplementary Figure S2B-C; Supplementary Tables S1-S2): 8 downregulated, LTB, SEC31B, MMP9, QPCT, NTN3, MYB, CD4, and STXBP6; 19 upregulated, ZNF222, HRH1, CYP27B1, PTGER2, NR4A3, CSF1, IL4R, CCL7, IL2RB, SMPDL3B, NOD2, MSC, PRF1, FOSB, CD27, BIRC3, NPL, ZNF442, and BFSP1. RD3 regulated immune cell related transcriptome pertaining to immune surveillance, immune escape and inflammation combined with our documented evidence of de novo acquisition of RD3-loss with therapy pressure and RD3-loss orchestrates NB evolut","journal":"Cancer Communications","year":2024,"id":461535,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1291032,"name":"Sreenidhi Mohanvelu","orcid":null,"position":1,"is_corresponding":false},{"id":382957,"name":"Dinesh Babu Somasundaram","orcid":"0000-0001-7618-1694","position":2,"is_corresponding":false},{"id":1290467,"name":"Sivaroopan Aravindan","orcid":"0009-0005-2433-4456","position":3,"is_corresponding":false},{"id":382956,"name":"Natarajan Aravindan","orcid":"0000-0001-9150-3911","position":4,"is_corresponding":false},{"id":1291031,"name":"Poorvi Subramanian","orcid":null,"position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:04:16.410510Z","pmid":"39445727","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}