Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer

Lu, Jiaye; Li, Jingwei; Lin, Ziyou; Li, Huaxuan; Lou, Linlin; Ding, Wen; Ouyang, Shumin; Wu, Yangjie; Wen, Yonggang; Chen, Xiaobing; Yue, Peibin; Wang, Yuanxiang; Liu, Peiqing; Lu, Jin-Jian; Zhang, Jian; Feng, Weineng; Zhang, Xiaolei

doi:10.1016/j.canlet.2023.216205

Cited by 24 publications

(11 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our luciferase reporter studies suggest that HDAC6 may regulate CD47 expression at the transcriptional level. Although the mechanism by which IFNγ upregulates CD47 is not fully understood, some pathways that are modulated by HDAC6 may be involved in this signaling pathway [ 39 , 43 , 56 ]. For example, our group has shown that HDAC6 interacts with STAT3 and that HDAC6is prevent PD-L1 upregulation upon IL-6 or IFNγ treatment [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting HDAC6 improves anti-CD47 immunotherapy

Gracia-Hernandez,

Yende,

Gajendran

et al. 2024

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Cancer cells can overexpress CD47, an innate immune checkpoint that prevents phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) expressed in macrophages and other myeloid cells. Several clinical trials have reported that CD47 blockade reduces tumor growth in hematological malignancies. However, CD47 blockade has shown modest results in solid tumors, including melanoma. Our group has demonstrated that histone deacetylase 6 inhibitors (HDAC6is) have immunomodulatory properties, such as controlling macrophage phenotype and inflammatory properties. However, the molecular and cellular mechanisms controlling these processes are not fully understood. In this study, we evaluated the role of HDAC6 in regulating the CD47/SIRPα axis and phagocytosis in macrophages. Methods We tested the role of HDAC6is, especially Nexturastat A, in regulating macrophage phenotype and phagocytic function using bone marrow-derived macrophages and macrophage cell lines. The modulation of the CD47/SIRPα axis and phagocytosis by HDAC6is was investigated using murine and human melanoma cell lines and macrophages. Phagocytosis was evaluated via coculture assays of macrophages and melanoma cells by flow cytometry and immunofluorescence. Lastly, to evaluate the antitumor activity of Nexturastat A in combination with anti-CD47 or anti-SIRPα antibodies, we performed in vivo studies using the SM1 and/or B16F10 melanoma mouse models. Results We observed that HDAC6is enhanced the phenotype of antitumoral M1 macrophages while decreasing the protumoral M2 phenotype. In addition, HDAC6 inhibition diminished the expression of SIRPα, increased the expression of other pro-phagocytic signals in macrophages, and downregulated CD47 expression in mouse and human melanoma cells. This regulatory role on the CD47/SIRPα axis translated into enhanced antitumoral phagocytic capacity of macrophages treated with Nexturastat A and anti-CD47. We also observed that the systemic administration of HDAC6i enhanced the in vivo antitumor activity of anti-CD47 blockade in melanoma by modulating macrophage and natural killer cells in the tumor microenvironment. However, Nexturastat A did not enhance the antitumor activity of anti-SIRPα despite its modulation of macrophage populations in the SM1 tumor microenvironment. Conclusions Our results demonstrate the critical regulatory role of HDAC6 in phagocytosis and innate immunity for the first time, further underscoring the use of these inhibitors to potentiate CD47 immune checkpoint blockade therapeutic strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting HDAC6 improves anti-CD47 immunotherapy

Gracia-Hernandez,

Yende,

Gajendran

et al. 2024

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“… 5 Besides, upregulation of CD47 facilitates tumour immune escape by influencing the polarisation of macrophages. 6 Therefore, considering the important roles of CD47 in regulating macrophage function, tumour immunophenotyping method was performed using RNA sequencing data to compare the infiltration of macrophage subsets. Our results revealed higher infiltration of M2‐polarised macrophages in patients with high CD47 expression ( p = .0050), characterised by increased cell surface molecules such as CD200R1, TGFBR1 and CD226 (Figure 3A,B ).…”

Section: Figurementioning

confidence: 99%

CD47 overexpression is related to tumour‐associated macrophage infiltration and diffuse large B‐cell lymphoma progression

Shen,

Ji,

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

CD47 overexpression is related to tumour-associated macrophage infiltration and diffuse large B-cell lymphoma progressionDear Editor, Cluster of differentiation 47 (CD47) belongs to the immunoglobulin superfamily and is considered an adverse prognostic risk factor for diffuse large B-cell lymphoma (DLBCL) patients. 1 Accumulating evidence reveals that F I G U R E 1 Clinical outcomes according to CD47 expression in diffuse large B-cell lymphoma (DLBCL) patients with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. (A and B) Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) according to CD47 mRNA expression in DLBCL patients treated with R-CHOP regimen. Data are analysed by log-rank test. (C and D) Univariate analysis of predictors for PFS and OS. Hazard ratios (HR), 95% confidence intervals (95% CIs) and p-values are indicated on the right of each forest plot.

show abstract

“…Additionally, compared to other ICIs, RRx-001 exerts more antitumor effects, either alone or in combination, for its multiple roles in anti-angiogenesis, sensitization to chemotherapeutic agents, and immune sensitization 39 – 42 . In addition to RRx-001, some traditional anti-tumor small molecule drugs, including 4-methylumbelliferone (4Mu), metformin, and gefitinib, have been shown to reduce the expression of CD47 protein and enhance the phagocytic activity of TAMs 99 . Relative research remains at the stage of preliminary discovery, which warrants further specific research.…”

Section: Small Molecule Drugs Directly Targeting Immune Checkpointsmentioning

confidence: 99%

Development of small molecule drugs targeting immune checkpoints

Chen,

Zhao,

Liu

et al. 2024

Cancer Biol Med

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.

show abstract

Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer

Cited by 24 publications

References 42 publications

Targeting HDAC6 improves anti-CD47 immunotherapy

Targeting HDAC6 improves anti-CD47 immunotherapy

CD47 overexpression is related to tumour‐associated macrophage infiltration and diffuse large B‐cell lymphoma progression

Development of small molecule drugs targeting immune checkpoints

Contact Info

Product

Resources

About