김민수 (University of Rochester Medical Center)

한빛사논문

조회197

University of Rochester Medical Center

CV File 193 kb

Proc. Natl. Acad. Sci. USA, Aug 27 2024, 121 (35) | https://doi.org/10.1073/pnas.2406748121 Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors

Ankit Dahal ¹, Yeonsun Hong ¹, Jocelyn S Mathew ¹, Adam Geber ¹, Sarah Eckl ¹, Stephanie Renner ¹, Cooper J Sailer ², Allison T Ryan ¹, Sana Mir ¹, Kihong Lim ¹, David C Linehan ^{3 4}, Scott A Gerber ^{1 3 4}, Minsoo Kim ^{1 3 *}

¹Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY.

²Department of Pathology, University of Rochester Medical Center, Rochester, NY.

³Department of Surgery, University of Rochester Medical Center, Rochester, NY.

⁴Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.

^*Corresponding author: correspondence to Minsoo Kim

Abstract

Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1- O-alkyl-2-acetyl- sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-27)
연구진국외 연구진
분야 의약학 > 면역의학

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