{"doi":"10.1101/2024.12.02.626446","title":"A TROP2/Claudin Program Mediates Immune Exclusion to Impede Checkpoint Blockade in Breast Cancer","abstract":"ABSTRACT Background Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of anti-cancer Antibody Drug Conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-PD1 therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC Sacituzumab govitecan (SG), enhances the anti-PD1 response and improves T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate anti-tumor immunity and enhance immunotherapy response. What is already known on this topic Barrier-mediated immune exclusion is emerging as a mechanism of immune evasion in cancer such as triple-negative breast cancer (TNBC), but its molecular underpinnings remain poorly understood. TROP2 is a surface glycoprotein targeted by antibody-drug conjugates such as Sacituzumab govitecan, yet its functional role beyond drug delivery has been unclear. What this study adds This study identifies TROP2 as a key regulator of tight junction-mediated immune exclusion in TNBC, independent of its intracellular signaling function. TROP2 promotes an immune-cold tumor microenvironment by enforcing mechanical barriers that limit T cell infiltration. How this study might affect research, practice or policy These findings establish TROP2 as a functional driver of immune evasion and provide a mechanistic rationale for combining TROP2-targeting therapies with immune checkpoint inhibitors to overcome resistance in immune-excluded tumors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485789,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"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":1329325,"name":"Win Thant","orcid":null,"position":1,"is_corresponding":false},{"id":1329326,"name":"Elena Bitman","orcid":null,"position":2,"is_corresponding":false},{"id":1328848,"name":"Ting Liu","orcid":"0000-0001-7870-3783","position":3,"is_corresponding":false},{"id":1328849,"name":"Jie Liu","orcid":"0000-0002-9685-5825","position":4,"is_corresponding":false},{"id":759467,"name":"Eleftherios I. Paschalis","orcid":"0000-0002-4544-4452","position":5,"is_corresponding":false},{"id":1081863,"name":"Katherine Xu","orcid":"0000-0001-8622-1303","position":6,"is_corresponding":false},{"id":1179201,"name":"Cole Nawrocki","orcid":"0000-0001-7776-2095","position":7,"is_corresponding":false},{"id":59692,"name":"Linda T. Nieman","orcid":"0000-0002-0141-8308","position":9,"is_corresponding":false},{"id":43401,"name":"David T. Ting","orcid":"0000-0002-3261-2322","position":10,"is_corresponding":false},{"id":888502,"name":"Bruna de Gois Macedo","orcid":"0000-0001-6907-1630","position":11,"is_corresponding":false},{"id":735395,"name":"Yang Cheng","orcid":"0000-0002-5906-7694","position":12,"is_corresponding":false},{"id":398016,"name":"Kevin Jiang","orcid":"0000-0002-1236-6160","position":13,"is_corresponding":false},{"id":1035149,"name":"Fengfei Sun","orcid":null,"position":14,"is_corresponding":false},{"id":621805,"name":"Nayana Thimmiah","orcid":"0009-0008-4917-6732","position":15,"is_corresponding":false},{"id":1328850,"name":"Sheng Sun","orcid":"0000-0002-5871-0844","position":16,"is_corresponding":false},{"id":1017842,"name":"Rachel O. Abelman","orcid":"0000-0002-3946-7420","position":17,"is_corresponding":false},{"id":1329327,"name":"Veerle I. Bossuyt","orcid":null,"position":18,"is_corresponding":false},{"id":256299,"name":"Steven J. Isakoff","orcid":"0000-0002-6677-1014","position":19,"is_corresponding":false},{"id":506093,"name":"Laura M. Spring","orcid":"0000-0001-8904-3514","position":20,"is_corresponding":false},{"id":105199,"name":"Aditya Bardia","orcid":"0000-0003-4885-1157","position":21,"is_corresponding":false},{"id":506095,"name":"Leif W. 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