Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy

Chen, Siqi; Lai, Seigmund Wai Tsuen; Brown, Christine E.; Feng, Mingye

doi:10.3389/fimmu.2021.635173

Cited by 53 publications

(48 citation statements)

References 164 publications

(236 reference statements)

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“…Kruppel-like factor 13 (KLF13) has low activity in moderate patients and high activity in severe patients. Low expression of KLF13 is implicated in diminishing pro-inflammatory and enhancing phagocytic activity in macrophages, a necessary balance in maintaining an efficient immune response ( 85 , 86 ). BCL6 has low activity in severe and moderate COVID-19 patients; its loss implies hyper-proliferation, followed by the expression of STAT3 to secrete IL-6, contributing to the cytokine storm in severe COVID-19 patients ( 87 ).…”

Section: Resultsmentioning

confidence: 99%

On Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers

et al. 2021

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COVID-19 is a disease with a spectrum of clinical responses ranging from moderate to critical. To study and control its effects, a large number of researchers are focused on two substantial aims. On the one hand, the discovery of diverse biomarkers to classify and potentially anticipate the disease severity of patients. These biomarkers could serve as a medical criterion to prioritize attention to those patients with higher prone to severe responses. On the other hand, understanding how the immune system orchestrates its responses in this spectrum of disease severities is a fundamental issue required to design new and optimized therapeutic strategies. In this work, using single-cell RNAseq of bronchoalveolar lavage fluid of nine patients with COVID-19 and three healthy controls, we contribute to both aspects. First, we presented computational supervised machine-learning models with high accuracy in classifying the disease severity (moderate and severe) in patients with COVID-19 starting from single-cell data from bronchoalveolar lavage fluid. Second, we identified regulatory mechanisms from the heterogeneous cell populations in the lungs microenvironment that correlated with different clinical responses. Given the results, patients with moderate COVID-19 symptoms showed an activation/inactivation profile for their analyzed cells leading to a sequential and innocuous immune response. In comparison, severe patients might be promoting cytotoxic and pro-inflammatory responses in a systemic fashion involving epithelial and immune cells without the possibility to develop viral clearance and immune memory. Consequently, we present an in-depth landscape analysis of how transcriptional factors and pathways from these heterogeneous populations can regulate their expression to promote or restrain an effective immune response directly linked to the patients prognosis.

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Section: Resultsmentioning

confidence: 99%

On Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers

et al. 2021

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“…Given these findings, it is crucial to identify molecules that affect macrophage plasticity in the tumor milieu in order to design macrophage-oriented treatment and diagnosis strategies (225). Although FDA approved cancer immunotherapies primarily target the adaptive immunity, the importance of innate immunity in terms of anti-tumor strategies started to attract a great deal of attention (226). Various approaches have been explored over the recent years in order to target TAMs (227,228).…”

Section: Gunaydinmentioning

confidence: 99%

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Günaydın

2021

Front. Oncol.

123

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Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

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“…Tumor‐resident Tregs highly express CTLA4. Therefore, it is likely that LipC6‐primed TAMs destroy αCTLA‐4 Ab‐opsonized Tregs via Ab dependent cellular phagocytosis (ADCP) as it was found in other studies 42,43 . In contrast, Hiroyoshi Nishikawa group found PD‐1 blockade induces increased tumor‐infiltrating Tregs 44,45 which may compromise LipC6‐caused immune activation.…”

Section: Discussionmentioning

confidence: 84%

“…Therefore, it is likely that LipC6-primed TAMs destroy αCTLA-4 Ab-opsonized Tregs via Ab dependent cellular phagocytosis (ADCP) as it was found in other studies. 42,43 In contrast, Hiroyoshi Nishikawa group found PD-1 blockade induces increased tumor-infiltrating Tregs 44,45 which may compromise LipC6-caused immune activation. This assumption is supported by our finding in the current studies in which LipC6 in combination with αPD-1 Ab failed to promote CD8 + T cell increase, advance its IFN-γ production, and suppress Treg induction (Figure S2).…”

Section: Molecular Events In Association With T Cell Activation Induc...mentioning

confidence: 98%

Nanoliposome C6‐Ceramide in combination with anti‐CTLA4 antibody improves anti‐tumor immunity in hepatocellular cancer

Kim

et al. 2022

The FASEB Journal

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Combination therapy represents an effective therapeutic approach to overcome hepatocellular cancer (HCC) resistance to immune checkpoint blockade (ICB). Based upon previous work demonstrating that nanoliposome C6‐ceramide (LipC6) not only induces HCC apoptosis but also prevents HCC‐induced immune tolerance, we now investigate the potential of LipC6 in combination with ICB in HCC treatment. We generated orthotopic HCC‐bearing mice, which have typical features in common with human patients, and then treated them with LipC6 in combination with the antibodies (Abs) for programmed cell death protein 1 (PD‐1) or cytotoxic T‐lymphocyte antigen 4 (CTLA4). The tumor growth was monitored by magnetic resonance imaging (MRI) and the intrahepatic immune profiles were checked by flow cytometry in response to the treatments. Realtime PCR (qPCR) was used to detect the expression of target genes. The results show that LipC6 in combination with anti‐CTLA4 Ab, but not anti‐PD‐1 Ab, significantly slowed tumor growth, enhanced tumor‐infiltrating CD8+ T cells, and suppressed tumor‐resident CD4+CD25+FoxP3+ Tregs. Further molecular investigation indicates that the combinational treatment suppressed transcriptional factor Krüppel‐like Factor 2 (KLF2), forkhead box protein P3 (FoxP3), and CTLA4. Our studies suggest that LipC6 in combination with anti‐CTLA4 Ab represents a novel therapeutic approach with significant potential in activating anti‐HCC immune response and suppressing HCC growth.

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Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy

Cited by 53 publications

References 164 publications

On Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers

On Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Nanoliposome C6‐Ceramide in combination with anti‐CTLA4 antibody improves anti‐tumor immunity in hepatocellular cancer

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