{"doi":"10.1002/cac2.12592","title":"4‐1BB transcriptomic expression patterns across malignancies: Implications for clinical trials of 4‐1BB agonists","abstract":"4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [1, 2]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [3-7]. Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File. There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (n = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy. Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (n = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively). To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic, with 18.6% (8/43) and 14.5% (8/55), respectively, representing the only two malignancies with >15% of patients having this expression profile (Figure 1E). Otherwise, the proportions of patients having high 4-1BB expression along with low/moderate 4-1BBL expression were 12.5% (3/24) in sarcoma, 12.5% (3/24) in uterine, 10.0% (2/20) in lung, 8.0% (2/25) in stomach, 7.9% (11/140) in colorectal, and 0% (0/49) in breast. There was variability of expression patterns both within and between tumor types. It is, therefore, conceivable that patient selection for 4-1BB agonist trials based in part on transcript levels may merit investigation. We examined 12 genes that produce immunomodulatory molecules related to the TNF receptor superfamily or interacting co-stimulatory molecules, as well as markers related to ICIs in the clinic (Supplemental Table S3). The results of the univariable and the subsequent multivariable logistic regression are shown in Figure 1F. High RNA expression of 4-1BB was not associated with any specific tumor types. Among immune markers, ","journal":"Cancer Communications","year":2024,"id":466098,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"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":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":235243,"name":"Suzanna Lee","orcid":"0000-0002-9502-4907","position":4,"is_corresponding":false},{"id":1055333,"name":"Mary Nesline","orcid":"0000-0003-0523-4597","position":5,"is_corresponding":false},{"id":1055332,"name":"Sarabjot Pabla","orcid":"0000-0002-7746-9144","position":6,"is_corresponding":false},{"id":322907,"name":"Jeffrey M. Conroy","orcid":"0000-0003-1764-9706","position":7,"is_corresponding":false},{"id":1055334,"name":"Paul DePietro","orcid":"0000-0001-9072-0631","position":8,"is_corresponding":false},{"id":1297899,"name":"Heidi Ko","orcid":"0000-0002-7247-9175","position":9,"is_corresponding":false},{"id":235244,"name":"Jason K. Sicklick","orcid":"0000-0003-4403-0271","position":10,"is_corresponding":false},{"id":108759,"name":"Razelle Kurzrock","orcid":"0000-0003-4110-1214","position":11,"is_corresponding":false},{"id":1297898,"name":"Yuji Uehara","orcid":"0000-0001-8047-8730","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T02:04:54.606394Z","pmid":"39097973","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":[]}