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 2024-01-19T14:02:56Z 2024-01-19T14:02:56Z 2022-01-10 2021-08 2051-1426 https://pubs.kist.re.kr/handle/201004/116628 Purpose Here, 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 design A 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. Results CAT 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 alpha PD-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. Conclusions Collectively, 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. English BMJ PUBLISHING GROUP CANCER-ASSOCIATED THROMBOSIS VENOUS THROMBOEMBOLISM LYMPHOCYTE DEVELOPMENT DRUG-DELIVERY T-CELLS MECHANISMS ANTIANGIOGENESIS NORMALIZATION CHEMOTHERAPY HIF-1-ALPHA Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia Article 10.1136/jitc-2021-002332 1 JOURNAL FOR IMMUNOTHERAPY OF CANCER, v.9, no.8 JOURNAL FOR IMMUNOTHERAPY OF CANCER 9 8 scie scopus 000680894800002 2-s2.0-85111991388 Oncology Immunology Oncology Immunology Article CANCER-ASSOCIATED THROMBOSIS VENOUS THROMBOEMBOLISM LYMPHOCYTE DEVELOPMENT DRUG-DELIVERY T-CELLS MECHANISMS ANTIANGIOGENESIS NORMALIZATION CHEMOTHERAPY HIF-1-ALPHA immunomodulation tumor microenvironment adjuvants immunologic