The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages

Sri Murugan Poongkavithai Vadevoo, Gowri Rangaswamy Gunassekaran, Chae Eun Lee, Na Hye Lee, Jiyoun Lee, Sehyun Chae, Jae Yong Park, Jae Hyung Koo, Byungheon Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Expression and function of odorant receptors (ORs), which account for more than 50% of G protein-coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumorderived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage-tumor axis. Using Olfr78+/+ and Olfr78-/- bone marrow-derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, whichwas themain factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78-lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

Original languageEnglish
Article numbere2102434118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number37
DOIs
Publication statusPublished - 2021 Sep 14

Keywords

  • GPCR
  • Lactate
  • Olfr78
  • OR51E2
  • TAMs

ASJC Scopus subject areas

  • General

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