{"doi":"10.1172/jci.insight.163518","title":"Reprogramming of PD-1+ M2-like tumor-associated macrophages with anti–PD-L1 and lenalidomide in cutaneous T cell lymphoma","abstract":"Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti-programmed cell death ligand 1 (anti-PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti-PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti-PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti-PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.","journal":"JCI Insight","year":2023,"id":328665,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"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":108571,"name":"Xiwei Wu","orcid":"0000-0002-7071-1671","position":1,"is_corresponding":false},{"id":108565,"name":"Hanjun Qin","orcid":"0000-0002-0370-0913","position":2,"is_corresponding":false},{"id":409402,"name":"Yate‐Ching Yuan","orcid":"0000-0002-3698-9784","position":3,"is_corresponding":false},{"id":582368,"name":"Daniel Schmolze","orcid":"0000-0002-6947-2546","position":4,"is_corresponding":false},{"id":717714,"name":"Chingyu Su","orcid":"0000-0001-8354-8503","position":5,"is_corresponding":false},{"id":536647,"name":"Jasmine M. Zain","orcid":"0000-0003-4308-629X","position":6,"is_corresponding":false},{"id":1050589,"name":"Lilach Moyal","orcid":"0000-0002-3076-1527","position":7,"is_corresponding":false},{"id":291866,"name":"Emmilia Hodak","orcid":"0000-0002-1645-8038","position":8,"is_corresponding":false},{"id":289775,"name":"James F. Sanchez","orcid":"0000-0002-2254-6894","position":9,"is_corresponding":false},{"id":294150,"name":"Peter P. Lee","orcid":"0000-0002-2660-4377","position":10,"is_corresponding":false},{"id":634407,"name":"Mingye Feng","orcid":"0000-0002-3334-9917","position":11,"is_corresponding":false},{"id":226996,"name":"Steven T. Rosen","orcid":"0000-0002-8818-7724","position":12,"is_corresponding":false},{"id":291864,"name":"Christiane Querfeld","orcid":"0000-0001-9698-5809","position":13,"is_corresponding":false},{"id":717712,"name":"Zhen Han","orcid":"0000-0002-9230-2270","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:08:56.940647Z","pmid":"37427589","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":[]}