Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Sarkar, Susobhan; Döring, Axinia; Fj, Zemp; Silva, C; Lun, Xiao-Kang; Wang, X; Kelly, John J.; Hader, Walter; Hamilton, Mark G.; Mercier, Philippe; Jf, Dunn; Kinniburgh, David; N, van Rooijen; Robbins, Sarah R; Cairncross, Gregory; Weiss, Samuel; Yong, V. Wee

doi:10.5214/ans.0972.7531.200407

Cited by 12 publications

(6 citation statements)

References 3 publications

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“…29 CSCs inhibit cytotoxic T cell proliferation while stimulate activation of T regulatory (Treg) cells 30 and promote recruitment of immunosuppressive TAMs 31 as well as enhance the transition of TAMs from the antitumor (M1) to the protumor (M2) phenotype. 9,32 In this study, we found CD68 C TF macrophages had a positive relation to CD44v6 TF . It revealed that the stem-like tumor cells seemed to recruit CD68 C macrophages to the invasive front in CRC.…”

Section: Discussionsupporting

confidence: 53%

Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma

Zhang

et al. 2017

OncoImmunology

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The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68 macrophages, CD3, CD4 or CD8 T lymphocytes, CD20 B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68 macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68 macrophages were associated with more CD44v6 expression (p < 0.001), lower Snail expression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68 macrophages were significantly related to more CD3 T lymphocytes (p = 0.002), CD8 T lymphocytes (p < 0.001) and CD20 B lymphocytes counts (p = 0.004). Strong CD68 macrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68 macrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68 macrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor-associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients.

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Section: Discussionsupporting

confidence: 53%

Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma

Zhang

et al. 2017

OncoImmunology

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“…However, the characteristic of considerable diversity and plasticity of microglia indicates that microglia function in distinct roles. It is reported that pro-inflammatory microglia or M1 microglia demonstrate anti-tumorigenic potential ( 43 ). Re-polarization of pro-tumorigenic, anti-inflammatory M2 TAM to anti-tumorigenic M1 TAM can reinforce the anti-tumor immunity ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models

Chen

et al. 2020

Front. Oncol.

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Glioblastoma (GBM) is an aggressive malignancy with poor prognosis. New therapeutic strategies for GBM are urgently needed. Although clinical studies have demonstrated the feasibility and safety of chimeric antigen receptor (CAR) T cell therapy for GBM, its efficacy has not been that impressive. The major limitation for anti-tumor efficacy of CARTs is the immunosuppressive milieu of the GBM tumor microenvironment (TME). TGFβ, a substantial component in GBM, compromises the immune response and contributes to immune evasion and tumor progression. To overcome this limitation and improve the efficacy of CART cells for GBM, we optimized an EGFRvIII-specific CAR construct with TGFRII ectodomain as a TGFβ-trap and generated TGFβ-resistant CARTs for GBM therapy. We demonstrated that this TGFβ-trapped architecture enhanced anti-tumor efficacy of EGFRvIII-specific CART and prolonged the survival of mice bearing GBM. In addition, the GBM-infiltrated microglia, typically considered tumorigenic, showed increased expression of M1 polarization markers after treatment with the TGFβ-trap CARTs group, indicating that these microglia were polarized toward a pro-inflammatory and anti-tumorigenic phenotype. Overall, these results indicated that arming CART cells with a TGFβ-trap diminishes the immunosuppressive effect and is a potential strategy to improve CART efficacy for GBM therapy.

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“…Other approaches that have suggested to curb glioma growth by altering the macrophage activation state rely on the use of cyclosporin A and amphotericin B [156][157][158] or on TEM that have been engineered to express IFN specifically at the tumor site [159]. A more thorough understanding of the molecular and functional heterogeneity of myeloid cells in gliomas will undoubtedly provide even more treatment opportunities.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Lahmar

Keirsse

Laoui

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

112

117

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Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Cited by 12 publications

References 3 publications

Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma

Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma

Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

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