{"doi":"10.1002/cam4.6000","title":"<scp>LAG</scp>‐3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics","abstract":"BACKGROUND: Lymphocyte activation gene 3 (LAG-3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T-cell activation. Many clinical trials of LAG-3 inhibitors have had modest effects, but recent data indicate that the LAG-3 antibody relatlimab, together with nivolumab (anti-PD-1), provided greater benefit than nivolumab alone in patients with melanoma. METHODS: In this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical-grade laboratory (OmniSeq: https://www.omniseq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) using a reference population (735 tumors; 35 histologies). RESULTS: A total of 116 of 514 tumors (22.6%) had high LAG-3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG-3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG-3 expression (15% of patients) (all p < 0.05 multivariate); 50% of melanomas were high LAG-3 expressors. There was significant independent association between high LAG-3 expression and high expression of other checkpoints, including programmed death-ligand 1 (PD-L1), PD-1, and CTLA-4, as well as high tumor mutational burden (TMB) ≥10 mutations/megabase, a marker for immunotherapy response (all p < 0.05 multivariate). However, within all tumor types, there was inter-patient variability in LAG-3 expression level. CONCLUSIONS: Prospective studies are therefore needed to determine if high levels of the LAG-3 checkpoint are responsible for resistance to anti-PD-1/PD-L1 or anti-CTLA-4 antibodies. Furthermore, a precision/personalized immunotherapy approach may require interrogating individual tumor immunograms to match patients to the right combination of immunotherapeutic agents for their malignancy.","journal":"Cancer Medicine","year":2023,"id":330972,"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":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235228,"name":"Shumei Kato","orcid":"0000-0003-1193-1815","position":1,"is_corresponding":false},{"id":1055330,"name":"Daisuke Nishizaki","orcid":"0000-0002-6746-3224","position":2,"is_corresponding":false},{"id":1055331,"name":"Hirotaka Miyashita","orcid":"0000-0002-0433-9779","position":3,"is_corresponding":false},{"id":641445,"name":"Pradip De","orcid":null,"position":4,"is_corresponding":false},{"id":235243,"name":"Suzanna Lee","orcid":"0000-0002-9502-4907","position":5,"is_corresponding":false},{"id":1055332,"name":"Sarabjot Pabla","orcid":"0000-0002-7746-9144","position":6,"is_corresponding":false},{"id":1055333,"name":"Mary Nesline","orcid":"0000-0003-0523-4597","position":7,"is_corresponding":false},{"id":322907,"name":"Jeffrey M. Conroy","orcid":"0000-0003-1764-9706","position":8,"is_corresponding":false},{"id":1055334,"name":"Paul DePietro","orcid":"0000-0001-9072-0631","position":9,"is_corresponding":false},{"id":7922,"name":"Scott M. Lippman","orcid":"0000-0002-1643-4124","position":10,"is_corresponding":false},{"id":108759,"name":"Razelle Kurzrock","orcid":"0000-0003-4110-1214","position":11,"is_corresponding":false},{"id":235241,"name":"Jacob J. Adashek","orcid":"0000-0003-4272-312X","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T01:09:14.691473Z","pmid":"37132280","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":[]}