Dataset Information

PAD4 controls tumor immunity via restraining the MHC-II machinery in macrophages

ABSTRACT: Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood if and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we found that peptidylarginine deiminase 4 (PAD4) manifested the highest expression among common PTM enzymes in TAMs and negatively correlated to clinical response to immune checkpoint blockade (ICB). Genetic and pharmacological inhibition of PAD4 in macrophages prevented tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage MHC-II expression and T-cell effector function. Mechanistically, PAD4 citrullinated STAT1 at arginine 121 (R121), thereby promoting the interaction between STAT1 and PIAS1; and the loss of PAD4 abolished this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC-II machinery in macrophages and enhancing T-cell activation. Thus, the PAD4-STAT1-PIAS1 axis is a previously unknown intrinsic immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Colon Cancer

SUBMITTER: Michael Pitter

LAB HEAD: Weiping Zou

PROVIDER: PXD049188 | Pride | 2024-05-22

REPOSITORIES: Pride

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			Action	DRS
	PRF_Q_2023_W_ZOU_943_58375.raw	Raw
	PRF_Q_2023_W_ZOU_943_58375_Perco_ptmRS.msf	Msf
	PRF_Q_2023_W_ZOU_943_58376.raw	Raw
	PRF_Q_2023_W_ZOU_943_58376_Perco_ptmRS.msf	Msf
	PRF_Q_2023_W_ZOU_943_58377.raw	Raw

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PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages.

Pitter Michael R MR Kryczek Ilona I Zhang Hongjuan H Nagarsheth Nisha N Xia Houjun H Wu Zhenyu Z Tian Yuzi Y Okla Karolina K Liao Peng P Wang Weichao W Zhou Jiajia J Li Gaopeng G Lin Heng H Vatan Linda L Grove Sara S Wei Shuang S Li Yongqing Y Zou Weiping W

Cell reports 20240313 3

Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages pre ...[more]

PMID: 38489266

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Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.