Immune checkpoint inhibitor response in sarcomas associates with immune infiltrates and increased expression of transposable elements and viral response pathways

Response to immune checkpoint inhibition (ICI) in sarcoma is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. One potential mechanism is epigenetic de-repression of transposable elements (TEs), which stimulates antitumor immunity. Here, we used transcriptomic data to assign immune-hot versus immune-cold status to 67 pre-treatment biopsies of sarcomas from patients treated on ICI trials. Progression-free survival and overall response was superior in the immune-hot group. Expression of TEs and epigenetic regulators significantly predicted immune-hot status in a regression model in which specific TE subfamilies and IKZF1, a chromatin-interacting transcription factor, were significantly contributory. TE and IKZF1 expression positively correlated with tumor immune infiltrates, inflammatory pathways, and clinical outcomes. Key findings were confirmed in a validation cohort (n=190). This work suggests that TE and IKZF1 expression warrant investigation as predictive biomarkers for ICI response and as therapeutic targets in sarcomas. ### Competing Interest Statement Sujana Movva: research funding from Ascentage Pharma, Tracon, Hutchinson Medi-pharma, Pfizer/Trillium and research support from Merck, Clovis, and Bristol Meyers Squibb. Jason Chan: research support from Ono pharmaceuticals. Mark Dickson: Research funding (to institution) from Eli Lilly, Aadi Bioscience, and Sumitomo Pharma. Mrinal Gounder: Personal Honoraria/Advisory Boards and/or Associated Research Paid to Institution from Aadi, Ayala, Bayer, Boehringer Ingelheim, Daiichi, Epizyme, Karyopharm, Regeneron, Rain, Springworks, Tracon and TYME; OTHER: Guidepoint, GLG, Third Bridge; Flatiron Health CME Honoraria: Medscape, More Health, Physicians Education Resource, MJ LifeSciences and touchIME; ROYALTIES: Wolters Kluwer; patents with MSKCC (GODDESS PRO); uncompensated research with Foundation Medicine GRANTS from Food and Drug Administration (R01 FD005105) and the National Cancer Institute, National Institutes of Health (P30CA008748) core grant (CCSG shared resources and core facility). Ping Chi: personal honoraria/advisory boards/consulting from Deciphera, NingboNewBay Medical Technology; institutional research funding from Pfizer/Array, Deciphera, Ningbo NewBay Medical Technology. Robert Maki: consulting fees from AADi, Bayer, Deciphera, Presage, Springworks, American Board of Internal Medicine, American Society for Clinical Oncology and UptoDate. Ciara Kelly: Institutional research funding from Merck, Amgen, Servier, Regeneron, Xencor, Curadev pharma; Consulting for Kartos pharmaceuticals, Deciphera. Sandra DAngelo: Consulting or Advisory Role for Aadi Bioscience Adaptimmune, Adicet Bio, GI Innovations, GlaxoSmithKline, Incyte, Medendi, Medidata, Nektar, Pfizer, Rain Therapeutics, Servier; Research Funding from EMD Serono, Amgen, Merck, Incyte, Nektar, Britsol-Meyers Squibb, Deciphera; Travel, Accommodations, Expenses from Adaptimmune, EMD Serono, Nektar; Participation on a DataSafety Monitoring Board or Advisory Board for GlaxoSmithKline, Nektar, Adaptimmune, Merck. William Tap: Consulting, Advisory Role, Honoraria: Aadi Biosciences, Abbisko, Amgen, AmMAx Bio, Avacta, Ayala Pharmaceuticals, Bayer, BioAlta, Boehringer Ingelheim, C4 Therapeutics, Cogent Biosciences, Curadev, Daiichi Sankyo, Deciphera, Eli Lilly, Epizyme Inc (Nexus Global Group), Foghorn Therapeutics, Ikena Oncology, IMGT, Inhirbix Inc., Ipsen Pharma, Jansen, Kowa Research Inst., Medpacto, Novo Holdings, PER, Servier, Sonata Therapeutics; research funding from Novartis, Eli Lilly, Plexxikon, Daiichi Sankyo, Tracon Pharma, Blueprint Medicines, Immune Design, BioAlta, Deciphera; Patents, Royalties, Other Intellectual Property: Companion Diagnostics for CDK4 inhibitors (14/854,329), Stock and Other Ownership Interests: Certis Oncology Solution, Atropos. All other authors declare no competing interests. ### Clinical Trial NCT03069378 [NCT03282344][1] NCT03414229 ### Funding Statement This work was supported by Merck, Amgen, NEKTAR, Incyte, Bristol Myers Squibb, Cycle for Survival, and Witherwax Fund. BAN received support from the NCI K08CA245212, the Connective Tissue Oncology Society Basic Science Research Award (with WDT), and the Damon Runyon Clinical Investigator Award. Additional support was provided by the Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748) and Hillman Cancer Center Support Grant (P30 CA047904) provided additional support. We acknowledge the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the Memorial Sloan Kettering Cancer Center gave ethical approval for this work. Please see manuscript text for a full description of the ethical oversight. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All RNA sequencing data, where informed consent has been obtained from the patient, is publicly available via dbGaP (accession number: phs003284). Three samples are not publicly available due to lack of consent for their release. All exome recapture sequencing data will be available via dbGaP under accession number phs001783 by the time of publication. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03282344&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F03%2F2024.01.02.24300710.atom