Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia

• Published in: Journal for immunotherapy of cancer Vol. 9; no. 8; p. e002332
• Main Authors: Choi, Jeong Uk, Lee, Na Kyeong, Seo, Hyungseok, Chung, Seung Woo, Al-Hilal, Taslim A, Park, Seong Jin, Kweon, Seho, Min, Nuri, Kim, Sang Kyoon, Ahn, Seohyun, Kim, Uk-Il, Park, Jin Woo, Kang, Chang-Yuil, Kim, In-San, Kim, Sang Yoon, Kim, Kyungjin, Byun, Youngro
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01-08-2021; BMJ Publishing Group
• Series: Original research
• Subjects: Adenosine; Animals; Anticoagulants; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Blood clots; Blood vessels; Cancer; Cancer therapies; Cell Hypoxia - drug effects; Chemotherapy; Clinical/Translational Cancer Immunotherapy; Cytokines; Drug dosages; Experiments; Flow cytometry; Humans; Hypoxia; Immunomodulation - drug effects; Immunotherapy; Immunotherapy - methods; Lymphocytes; Melanoma; Mice; Regression analysis; T cell receptors; Thrombosis; Tumor Microenvironment; Tumors; Variance analysis; Turkey; immunomodulation; tumor microenvironment; immunologic; adjuvants
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-002332

PurposeHere, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia.Experimental designA novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation. Tumor perfusion and hypoxia were analyzed with or without treating STP3725 in wild-type and P selectin knockout mice. Immunosuppressive cytokines and cells were analyzed to evaluate the alteration of the tumor microenvironment. Effector lymphocyte infiltration in tumor tissue was assessed by congenic CD45.1 mouse lymphocyte transfer model with or without anticoagulant therapy. Finally, various tumor models including K-Ras mutant spontaneous cancer model were employed to validate the role of the anticoagulation therapy in enhancing the efficacy of immunotherapy.ResultsCAT was demonstrated to be one of the perfusion barriers, which fosters immunosuppressive microenvironment by accelerating tumor hypoxia. Consistent treatment of oral anticoagulation therapy was proved to promote tumor immunity by alleviating hypoxia. Furthermore, this resulted in decrease of both hypoxia-related immunosuppressive cytokines and myeloid-derived suppressor cells while improving the spatial distribution of effector lymphocytes and their activity. The anticancer efficacy of αPD-1 antibody was potentiated by co-treatment with STP3725, also confirmed in various tumor models including the K-Ras mutant mouse model, which is highly thrombotic.ConclusionsCollectively, these findings establish a rationale for a new and translational combination strategy of oral anticoagulation therapy with immunotherapy, especially for treating highly thrombotic cancers. The combination therapy of anticoagulants with immunotherapies can lead to substantial improvements of current approaches in the clinic.