Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Zhang, Lijuan; Zhang, Kai; Zhang, Jieyou; Zhu, Jinrong; Xi, Qing; Wang, Huafeng; Zhang, Zimu; Cheng, Yingnan; Yang, Guangze; Liu, Hongkun; Guo, X. Edward; Zhou, Dongmei; Xue, Zhenyi; Li, Yan; Zhang, Qi; Da, Yurong; Liu, Li; Yin, Zhinan; Yao, Zhi; Zhang, Rongxin

doi:10.1038/s41467-021-24610-x

Cited by 22 publications

(19 citation statements)

References 57 publications

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“…To further confirm if the aforementioned influence of CFT073 wt on polarization of macrophages was caused by TcpC, rTcpC was prepared and its effects on macrophage polarization were also examined. In accordance with previous reports [ 27 , 31 , 32 ], LPS + IFN-γ significantly induced the expression of M1 markers CD80 and CD86, and IL-4 treatment promoted the expression of M2 markers CD163 and CD206 in both THP-1 and J774A.1 macrophage cell lines. However, 4 μg/mL rTcpC treatment profoundly attenuated LPS + IFN-γ=induced expression of CD80 and CD86 ( Figure 4 A–D), while promoting CD163 and CD206 expression ( Figure 4 E–H).…”

Section: Resultssupporting

confidence: 93%

“…It was reported that complete polarization of macrophages to the M1 type requires activation of the MAPK and NF-κB signaling pathways [ 19 , 27 , 31 , 61 ], and M2 macrophage polarization requires activation of the STAT signaling pathway [ 62 , 63 ]. To explore the signal transduction pathways underlying the regulatory effects of TcpC on M1/M2 polarization, the influence of TcpC on MAPK/NF-κB and Akt/STAT pathways was examined.…”

Section: Discussionmentioning

confidence: 99%

“…THP-1 cells were treated with 100 nM phorbol-12-myristate-13-acetate (PMA) (Sigma, Saint Louis, MO, USA) for 24 h to induce cellular differentiation into macrophages [ 26 ]. LPS (100 ng /mL)/IFN-γ (20 ng/mL) and IL-4 (20 ng/mL) were added into the corresponding wells to stimulate M1 and M2 macrophage polarization [ 27 ]. Macrophage cell lines (THP-1 and J774A.1) were separately co-cultured in transwell with CFT073 wt or CFT073 ∆ tcpc at a multiplicity of infection (MOI) of 100 for 24 h. To examine the influence of TcpC on M1 and M2 macrophage polarization, 1 × 10 6 cells of THP-1 or J774A.1 were treated with or without 4 μg/mL rTcpC for 24 h. Supernatants were obtained for an ELISA assay and cells were collected for flow cytometry and qRT-PCR.…”

Section: Methodsmentioning

confidence: 99%

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TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Fang

et al. 2022

Cells

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“…3A). In accordance with previous reports [40][41][42] , we observed that MP depletion significantly delayed tumor growth in wildtype mice (Prkcd +/+ ) (Fig. 3B,D).…”

Section: Pkcδ Deficiency Impairs Tumor Growth and Immune Suppression ...supporting

confidence: 93%

Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer

Chaib

Holt

Sipe

et al. 2022

Preprint

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Checkpoint immunotherapy unleashes T cell antitumor potential which has revolutionized cancer treatment showing unprecedented long-term responses. However, most patients do not respond to immunotherapy which often correlates with a dysfunctional or immunosuppressive myeloid compartment. The mononuclear phagocyte system (MPS) is a sub-class of myeloid cells comprising monocytes, macrophages and dendritic cells which plays a crucial role in tissue homeostasis. However, accumulating evidence suggests that mononuclear phagocytes contribute to all phases of tumorigenesis including orchestrating inflammatory events during de novo carcinogenesis, contribution to the progression of established tumors and promotion of resistance to checkpoint blockade. Thus, targeting the MPS could be an effective strategy to enhance checkpoint blockade efficacy and promote control of tumors. Here, we found that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by mononuclear phagocytes in several human and mouse tumors. PKCδ-/- mice were more resistant to growth of various cancers compared to wild-type mice and were more responsive to anti-PD-1 immunotherapy. Furthermore, we found that tumors from PKCδ-/- mice harbor a Th-1-skewed immune landscape including increased antigen cross-presentation and T cell activation. Depletion of mononuclear phagocytes in vivo altered tumor growth in wild-type mice, but not in PKCδ-/- mice. In addition, coinjection of PKCδ-/--deficient M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to wild-type M2-like macrophages coinjected with cancer cells. Finally, intrinsic loss of PKCδ-/- functionally reprogrammed macrophages and dendritic cells by promoting their antigen presenting and cross-presenting capacity and triggered type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram mononuclear phagocytes and augment checkpoint blockade efficacy.

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“…Unfortunately, M1 macrophages are in the minority while M2 macrophages are in the majority of tumors. M2 macrophages are involved in tumor invasion, metastasis, and immunosuppression in various manners to promote tumor growth and development. , At present, most studies have adopted various strategies to transform the formed M2-type into M1-type macrophages, − but these transformations are inefficient. Studies have revealed that the metabolic pathways of M2-type macrophages are reprogrammed in the process of maintaining their own vitality and function, such as highly dependent glutamine metabolism .…”

Section: Introductionmentioning

confidence: 99%

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency

Jiao

Bai

et al. 2022

ACS Appl. Mater. Interfaces

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Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

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Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Cited by 22 publications

References 57 publications

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency

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