{"doi":"10.1158/2159-8290.cd-19-1409","title":"Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade","abstract":"Abstract Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti–PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti–PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. Significance: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy. This article is highlighted in the In This Issue feature, p. 1079","journal":"Cancer Discovery","year":2020,"id":51769,"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":148,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"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":230452,"name":"Gabriel Abril-Rodríguez","orcid":"0000-0002-5607-0425","position":1,"is_corresponding":false},{"id":230455,"name":"Ameya S. Champhekar","orcid":"0000-0002-2758-0442","position":2,"is_corresponding":false},{"id":230450,"name":"Jennifer Tsoi","orcid":"0000-0001-7269-5161","position":3,"is_corresponding":false},{"id":226341,"name":"Katie M. Campbell","orcid":"0000-0001-6491-4432","position":4,"is_corresponding":false},{"id":230467,"name":"Anusha Kalbasi","orcid":"0000-0001-8692-1457","position":5,"is_corresponding":false},{"id":259513,"name":"Giulia Parisi","orcid":"0000-0002-2172-3078","position":6,"is_corresponding":false},{"id":226346,"name":"Jesse M. Zaretsky","orcid":"0000-0002-4889-2648","position":7,"is_corresponding":false},{"id":259514,"name":"Ángel García-Díaz","orcid":"0000-0001-6139-6764","position":8,"is_corresponding":false},{"id":226367,"name":"Cristina Puig-Saus","orcid":"0000-0002-3014-3649","position":9,"is_corresponding":false},{"id":261314,"name":"Gardenia Cheung-Lau","orcid":null,"position":10,"is_corresponding":false},{"id":261315,"name":"Thomas Wohlwender","orcid":null,"position":11,"is_corresponding":false},{"id":259515,"name":"Paige Krystofinski","orcid":"0000-0001-8613-0954","position":12,"is_corresponding":false},{"id":230461,"name":"Agustin Vega-Crespo","orcid":"0000-0003-1326-0517","position":13,"is_corresponding":false},{"id":259516,"name":"Christopher M. Lee","orcid":"0000-0002-7755-0030","position":14,"is_corresponding":false},{"id":259517,"name":"Pau Mascaro","orcid":"0009-0007-5107-2345","position":15,"is_corresponding":false},{"id":230449,"name":"Catherine S. Grasso","orcid":"0000-0001-8632-4126","position":16,"is_corresponding":false},{"id":226358,"name":"Beata Berent-Maoz","orcid":"0000-0002-5972-9029","position":17,"is_corresponding":false},{"id":261316,"name":"Begoña Comı́n-Anduix","orcid":null,"position":18,"is_corresponding":false},{"id":259518,"name":"Siwen Hu‐Lieskovan","orcid":"0000-0001-5836-4710","position":19,"is_corresponding":false},{"id":58599,"name":"Antoni Ribas","orcid":"0000-0003-3669-8458","position":20,"is_corresponding":false},{"id":230457,"name":"Davis Y. Torrejon","orcid":"0000-0002-4864-6236","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-18T20:41:30.009880Z","pmid":"32467343","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":[]}