Macrophage NPM1 drives anti-tumor immunity via the STAT3-CCRL2 axis.

BACKGROUND

Although nucleophosmin (NPM1) is a well-characterized oncogene in acute myeloid leukemia, much less is known about its role in solid tumor immunity. Here, we examined the function of NPM1 in regulating anti-tumor immunity within the tumor microenvironment.

METHODS

The proportion and functional changes of macrophages and T cells were detected by flow cytometry, the downstream regulatory genes of NPM1 were detected by RNA-seq, the binding ability of NPM1 and STAT3 was analyzed by Chip and luciferase assay.

RESULTS

NPM1 inhibition or genetic deficiency promoted tumor growth in MC38 colon cancer and LLC lung cancer mice models. Npm1+/- mice exhibited enhanced infiltration and polarization of immunosuppressive M2-like tumor-associated macrophages (TAMs) and impaired CD8+ T cell function. Mechanistically, NPM1 bound to p-TAT3/STAT3 and promoted transcription of CCRL2, a key regulator of macrophage polarization. Overexpression of Npm1 in mice suppressed tumor growth, reduced M2 TAMs polarization, and enhanced CD8+ T cell-mediated anti-tumor immunity.

CONCLUSION

Our findings revealed that NPM1 protects against tumor progression by regulating TAMs polarization and T cell function via the STAT3-CCRL2 axis.