{"doi":"10.1101/2020.05.06.081471","title":"Systemic immune dysfunction in cancer patients driven by IL6 and IL8 induction of an inhibitory receptor module in peripheral CD8 <sup>+</sup> T cells","abstract":"Many cancer patients do not develop a durable response to the current standard of care immunotherapies despite substantial advances in targeting immune inhibitory receptors 1-5 . A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer 6-12 . Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8 + T cell dysfunction, characterized by suboptimal T cell proliferation and chronic expression of IRs (eg. Programmed Death 1 [PD1] and Lymphocyte Activation Gene 3 [LAG3]) 13, 14 . Here, we demonstrate that up to a third of cancer patients express robust intracellular LAG3 (LAG3 IC ), but not surface LAG3 (LAG3 SUR ), in peripheral CD8 + T cells compared to CD4 + T cells and regulatory T cells (T regs ). LAG3 IC is associated with: (i) expression of a LAG3 IC -dominant IR module that includes PD1 IC , NRP1 IC , CD39 IC , and TIGIT IC ; (ii) decreased CD8 + but not CD4 + T cell function that can be reversed by anti-LAG3 (and/or anti-PD1), despite limited constitutive surface IR expression; and (iii) poor disease prognosis. Systemic immune dysfunction is restricted to CD8 + T cells, including a high percentage of peripheral naïve CD8 + T cells, indicating a TCR-independent mechanism that is driven by the cytokine IL6 and the chemokine IL8. Thus, the combination of an increased LAG3-dominant IR module and elevated systemic IL6 and/or IL8 may serve as predictive biomarkers and increase the possibility that cancer patients will benefit from therapeutic combinations targeting these systemic cytokines in the setting of PD1 and/or LAG3 blockade.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124835,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":109265,"name":"Anthony R. Cillo","orcid":"0000-0002-3213-3129","position":1,"is_corresponding":false},{"id":562877,"name":"Caleb Lampenfeld","orcid":"0000-0002-0613-4494","position":2,"is_corresponding":false},{"id":570066,"name":"Lauren Oliveri","orcid":"0000-0003-3111-0520","position":3,"is_corresponding":false},{"id":557788,"name":"Maria A. Velez","orcid":"0000-0001-5197-4719","position":4,"is_corresponding":false},{"id":570067,"name":"Sonali Joyce","orcid":"0000-0003-4839-825X","position":5,"is_corresponding":false},{"id":307519,"name":"Michael Calderon","orcid":"0000-0002-0820-7888","position":6,"is_corresponding":false},{"id":570068,"name":"Rebekah Dadey","orcid":"0000-0001-9912-7893","position":7,"is_corresponding":false},{"id":320291,"name":"Dhivyaa Rajasundaram","orcid":"0000-0001-7417-8002","position":8,"is_corresponding":false},{"id":242168,"name":"Daniel P. Normolle","orcid":"0000-0001-8675-5014","position":9,"is_corresponding":false},{"id":279286,"name":"Simon C. Watkins","orcid":"0000-0003-4092-1552","position":10,"is_corresponding":false},{"id":1832,"name":"James G. Herman","orcid":"0000-0001-8102-1740","position":11,"is_corresponding":false},{"id":247570,"name":"John M. Kirkwood","orcid":"0000-0002-3570-4476","position":12,"is_corresponding":false},{"id":258581,"name":"Evan J. Lipson","orcid":"0000-0003-2976-0911","position":13,"is_corresponding":false},{"id":109277,"name":"Robert L. Ferris","orcid":"0000-0001-6605-2071","position":14,"is_corresponding":false},{"id":109276,"name":"Tullia C. Bruno","orcid":"0000-0002-6433-0207","position":15,"is_corresponding":false},{"id":109278,"name":"Dario A.A. Vignali","orcid":"0000-0002-2771-5992","position":16,"is_corresponding":false},{"id":258579,"name":"Ashwin Somasundaram","orcid":"0000-0003-3167-406X","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:15:11.632153Z","pmid":null,"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":[]}