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

Jeong Uk Choi, Na Kyeong Lee, Hyungseok Seo, Seung Woo Chung, Taslim A. Al-Hilal, Seong Jin Park, Seho Kweon, Nuri Min, Sang Kyoon Kim, Seohyun Ahn, Uk Il Kim, Jin Woo Park, Chang Yuil Kang, In San Kim, Sang Yoon Kim, Kyungjin Kim, Youngro Byun

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 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. 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.

Original languageEnglish
Article numbere002332
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number8
DOIs
Publication statusPublished - 2021 Aug 2
Externally publishedYes

Keywords

  • adjuvants
  • immunologic
  • immunomodulation
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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