Tumor Cells Induce LAMP2a Expression in Tumor-Associated Macrophage for Cancer Progression

Abstract

Background: Tumor cells benefit from tumor-associated macrophages (TAMs) promoting tumor growth and modulating functions of other cells in tumor microenvironment (TME). However, how tumor cells regulate the property of TAMs during tumor invasion remains to be defined. Methods: Mouse tumor models and cancer patients' samples were analyzed to determine LAMP2a expression in TAMs. In vitro mouse primary macrophages were used to assess LAMP2a-modulated macrophage activation, and to verify LAMP2a's target proteins. The effect of LAMP2a-knockdown on tumor progression and TME maintaining was determined by using mouse tumor models. Findings: Lysosome associated membrane protein type 2A (LAMP2a) is upregulated in TAMs by tumor cells and important for tumor progression. LAMP2a expression in TAMs, but not in tumor cells, is associated with poor prognosis in breast cancer. LAMP2a inactivation induced by either shRNA or CRISPR/Cas9 prevents TAMs activation and tumor growth. LAMP2a degrades PRDX1 (peroxiredoxin 1) and CRTC1 (CREB-regulated transcription coactivator 1) to promote macrophage pro-tumorigenic activation. Interpretation: Our study suggests that tumor cells utilize LAMP2a-PRDX1/CRTC1 axis to modulate TAMs activation and promote tumor growth, reveals the role of LAMP2a in macrophage study and TAM-targeting tumor immunotherapy. Funding Statement: National Key Research and Development Program of China (No. 2016YFA0201402); National Natural Science Foundation of China (No. 81602492). Declaration of Interests: All authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were approved by the institutional Animal Care and Use Committee. All patient samples concerned studies were approved by West China Hospital IRB committee. All human subjects (except for tissue microarray) were obtained from patients who were receiving treatment in West China Hospital, with all patients fully informed consent.