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

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. Tumor-derived 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, which was the main 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.

Odorant receptors in cancer

“…Previous studies and our analysis show that high levels of OR51E2 expression were also associated with poor prognosis in breast cancer patients ( Fig. 2A ) ( 25 ).…”

“…Compared with xenografts of LLC murine Lewis lung carcinoma cell on wild-type mice, xenografts of these cells on mice with knockout of Olfr78, a mouse analog of OR51E2, showed reduced tumor growth and metastasis. In addition, TCGA analysis showed that lower OR51E2 expression correlated significantly with better survival ( 25 ). Solid-phase microextraction GC/MS identified a cancer-specific odorant, 2-ethyl-1-hexanol, in the SK-MES cancer cell line, and screening of human ORs found that OR4D11P was a sensitive and selective receptor of 2-ethyl-1-hexanol ( 49 ).…”

“…Interestingly, OR4N2 and OR7A5 were found to be involved in the transcriptional regulatory network ( 51 ), and OR51E2 was involved in glio-blastoma progression. Analysis of glioblastoma patients in the TCGA database showed that high expression of OR51E2 was associated with poor prognosis ( 25 ). In addition, a four-gene signature (ASPM, CCNB1, EXO1, and KIF23) in patients with LGG correlated negatively with response to treatment with temozolomide (TMZ), which is frequently used as primary chemotherapy for LGG.…”

“…Studies have shown that ORs are expressed in tumor cells and tissues, including hepatocarcinoma cells ( 19 ), breast carcinoma tissues ( 20 ), prostate cancer cells ( 21 ), enterochromaffin tumor cells ( 22 ), melanomas ( 23 ), and urinary bladder cancers ( 24 ). Functional evaluations have shown that ORs in these cancers regulate cancer cell invasiveness, metastasis, differentiation, and prognosis ( 25 , 26 ), as well as being involved in cell signaling, proliferation, and apoptosis ( 5 - 7 ). This review describes current knowledge about the expression of distinct ORs in cancers, as well as the canonical and non-canonical signaling pathways induced by these ORs.…”

Odorant G protein-coupled receptors as potential therapeutic targets for adult diffuse gliomas: a systematic analysis and review

“…Given that ORs may have potential oncogenic roles in solid tumors, and that ORs expressed in normal brain and during neurodegenerative disease have functions distinct from odor perception, we hypothesized that ectopic ORs would perform tumor-related functions in brain. As further evidence for the role of ectopic ORs in tumor-related functions in brain, we previously reported that Olfr78 (human homolog, OR51E2) induced M2 polarization, thereby promoting tumor progression and metastasis ( 49 ). M2-like tumor-associated macrophages are abundant in the glioma microenvironment, and mediate increased resistance to radiotherapy and immunotherapy ( 50 - 52 ).…”