Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel

Dai, Xiaomeng; Meng, Jingshu; Deng, Suke; Zhang, Lingling; Wan, Chao; Lu, Lisen; Huang, Jing; Hu, Yan; Zhang, Zhanjie; Li, Yan; Lovell, Jonathan F.; Wu, Gang; Yang, Kunyu; Huang, Jin

doi:10.7150/thno.42385

Cited by 65 publications

(55 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Related studies have reported that promoting polarization of TAMs from M2 into M1 MΦs tends to increase the expression of PD-L1 40 , 45 . Therefore, we monitored PD-L1 expression in BMDMs after P5091 treatment, but no significant changes were detected (data not shown).…”

Section: Resultsmentioning

confidence: 88%

“…Mouse bone marrow-derived macrophages (BMDMs) were generated as described previously 40 . BMDMs were cultured with 20 ng/mL IL-4 (214-14-20) and 20 ng/mL IL-13 (210-13-10), to be polarized into IL-4/13 M2 MΦs; 50 ng/mL IL-10 (210-10-10), to be polarized into IL-10 M2 MΦs; or 50 ng/mL LPS and 20 ng/mL IFN-γ (315-05-20), to be polarized into M1 MΦs.…”

Section: Methodsmentioning

confidence: 99%

“…Obtaining tumor infiltrating immune cells from tumor tissue was performed as previously described 40 .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization. Methods: The expression of DUB related genes in macrophages (MΦs) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b + F4/80 + CD86 + CD206 - ), and M2 (CD11b + F4/80 + CD86 - CD206 + ) MΦs, and IFN-γ + CD8 + T cells. A proliferation assay was used to determine the effect of M2 MΦs treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD). Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 MΦs. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MΦs, favoring CD8 + T cells proliferation in vitro . USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 MΦs and IFN-γ + CD8 + T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate MΦs reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity. Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…POLY mitigated the activity of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) in the same macrophage cell line. CaMKII contributes to the formation of M2 tumor-associated macrophages and necrosis of atherosclerotic plaques [ 33 , 34 , 35 ]. There are not many papers available on the effects of DMTS.…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice

Dombi

Sánta

Bátai

et al. 2021

IJMS

View full text Add to dashboard Cite

Pharmacotherapy of neuropathic pain is still challenging. Our earlier work indicated an analgesic effect of dimethyl trisulfide (DMTS), which was mediated by somatostatin released from nociceptor nerve endings acting on SST4 receptors. Somatostatin release occurred due to TRPA1 ion channel activation. In the present study, we investigated the effect of DMTS in neuropathic pain evoked by partial ligation of the sciatic nerve in mice. Expression of the mRNA of Trpa1 in murine dorsal-root-ganglion neurons was detected by RNAscope. Involvement of TRPA1 ion channels and SST4 receptors was tested with gene-deleted animals. Macrophage activity at the site of the nerve lesion was determined by lucigenin bioluminescence. Density and activation of microglia in the spinal cord dorsal horn was verified by immunohistochemistry and image analysis. Trpa1 mRNA is expressed in peptidergic and non-peptidergic neurons in the dorsal root ganglion. DMTS ameliorated neuropathic pain in Trpa1 and Sstr4 WT mice, but not in KO ones. DMTS had no effect on macrophage activity around the damaged nerve. Microglial density in the dorsal horn was reduced by DMTS independently from TRPA1. No effect on microglial activation was detected. DMTS might offer a novel therapeutic opportunity in the complementary treatment of neuropathic pain.

show abstract

“…In addition, M2‐TAMs can be converted into M1‐TAMs to exert a lethal effect when subjected to certain external stimuli [117]. Dai et al [118] constructed a melittin‐(RADA)6 (MR52) hydrogel loaded with Ca 2+ /calmodulin‐dependent protein kinase II (CAMKII) inhibitor KN93 (MR52‐KN93 [MRK]). Melittin has high biological activity and can direct kill tumours.…”

Section: Anti‐tumour Mechanism Of Injectable Hydrogelmentioning

confidence: 99%

Injectable hydrogels for anti‐tumour treatment: a review

Xie

2020

Biosurface and Biotribology

View full text Add to dashboard Cite

Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel

Cited by 65 publications

References 45 publications

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice

Injectable hydrogels for anti‐tumour treatment: a review

Contact Info

Product

Resources

About