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Identification of m6A modification patterns and RBM15 mediated macrophage phagocytosis in pancreatic cancer: An
Wei Wang1, Ying He2, Li-Chao Yao3
1Department of Hepatobiliary Surgery, East Hospital, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; Key Laboratory of Hubei Province for Digestive System Disease, Wuhan 430060, Hubei Province, China.
Abstract:
Pancreatic cancer (PC) responds weakly to conventional immunotherapy. RNA N6-methyladenosine (m6A) modification has an essential role in the immune response, while its potential role in PC tumor microenvironment (TME) immune cell infiltration remains unknown. In this study, we thoroughly assessed the m6A modification patterns of 472 PC samples using 19 m6A regulators, and we systematically correlated these modification patterns with TME immune cell infiltration characteristics. We also created the m6Ascore and evaluated the m6A modification patterns of individual tumors, identified three different m6A modification patterns, and explored the role of the important m6A "writer" RBM15 in the regulation of macrophage function in PC. Two independent PC cohorts confirmed that patients with higher m6Ascore showed significant survival benefit. We verified that knockdown of RBM15 has the ability to inhibit PC growth and to promote macrophage infiltration and enhance phagocytosis of PC cells by macrophages. In conclusion, m6A modifications play a non-negligible role in the formation of TME diversity and complexity in PC. We reveal that inhibition of RBM15 suppresses PC development and modulates macrophage phagocytosis, and provide a more effective immunotherapeutic strategy for PC.
Insights
RNA N6-methyladenosine (m6A) modifications influence pancreatic cancer
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Pancreatic cancer (PC) exhibits limited response to conventional immunotherapy.
- The role of RNA N6-methyladenosine (m6A) modification in PC tumor microenvironment (TME) immune cell infiltration is not well understood.
Purpose of the Study:
- To investigate m6A modification patterns in PC.
- To correlate m6A patterns with TME immune cell infiltration.
- To explore the function of m6A regulator RBM15 in PC.
Main Methods:
- Analysis of m6A modification patterns in 472 PC samples using 19 m6A regulators.
- Development and evaluation of an m6Ascore.
- Assessment of RBM15's role in regulating macrophage function in PC.
Main Results:
- Identified three distinct m6A modification patterns.
- Higher m6Ascore correlated with improved patient survival in two independent cohorts.
- RBM15 knockdown inhibited PC growth, increased macrophage infiltration, and enhanced macrophage phagocytosis.
Conclusions:
- m6A modifications significantly impact TME complexity in PC.
- Inhibiting RBM15 suppresses PC development and enhances macrophage-mediated anti-tumor immunity.
- Targeting m6A modifications, specifically RBM15, offers a potential immunotherapeutic strategy for PC.
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