Good news! Cancer is history (soon)!
"Highlights
- Study reveals previously unrecognized way for cancer to evade the immune system.
- Other cancers could also be using sugar-coated proteins to shield themselves from immune attack.
- Findings suggest CD43 is a potential target for new cancer immunotherapies.
...
Now, researchers have identified a key part of the cancer’s disguise: a protein called CD43 on the surface of leukemia cells that is coated so heavily in sugar molecules that it forms a physical barrier, shielding the cells from immune attack. ..."
From the abstract of the Perspective:
"Immune cells continually detect, engulf, and destroy invasive microbes and cancer cells. This process, called phagocytosis, is carried out by macrophages that must distinguish between proengulfment signals and inhibitory (“don’t-eat-me”) warnings.
Cluster of differentiation 47 (CD47), a cell-surface receptor, is the archetypal don’t-eat-me signal.
Many cancers upregulate CD47 expression to escape phagocytosis, and CD47 blockade promotes phagocytosis of cancer cells in mice.
However, CD47 blockers have not shown clinical benefits in patients with acute myeloid leukemia (AML), an aggressive cancer of blood immune cells. This discrepancy has raised the possibility that the molecular programs that inhibit phagocytosis differ between mice and humans. On page 174 of this issue, Chung et al. report that the mechanisms that control macrophage function in human and mouse cells are indeed different. They also identify cluster of differentiation 43 (CD43) as a potential target for human AML treatment."
From the editor's summary and abstract:
"Editor’s summary
Phagocytosis is a process used by immune cells called macrophages to destroy pathogens and cellular debris.
Tumor cells can evade killing by macrophage-mediated phagocytosis by deploying decoy signals to the immune system.
Chung et al. performed a CRISPR screen of human acute myeloid leukemia (AML) cells to identify phagocytic regulators ...
The surface protein CD43 was found to be coated in a high-density shield of sialic acid residues that effectively functioned as a “don’t eat me” signal to limit immune clearance.
Inactivation of CD43 function restored the ability of macrophages to phagocytize AML. Strategies that disable sialylated glycans may therefore have potential to enhance phagocytosis and targeting of AML. ...
Structured Abstract
INTRODUCTION
Macrophages in the tumor microenvironment exert antitumorigenic effects through phagocytosis and/or direct tumoricidal activity.
Phagocytosis of tumor cells occurs through both antibody-dependent cellular phagocytosis (ADCP) and antibody-independent cellular phagocytosis (AICP) mechanisms. Despite the strong evidence that macrophages can mediate tumor control in acute myeloid leukemia (AML) and other diseases, therapeutic agents that enhance macrophage phagocytosis, including anti-CD47 neutralizing antibodies, have not led to improved clinical outcomes. Thus, a more comprehensive understanding of the tumor-intrinsic factors that suppress human macrophage phagocytosis is needed.
RATIONALE
To systematically identify the key pathways that regulate phagocytosis by human macrophages, we performed genome-scale knockout CRISPR screens in human AML cell lines cocultured with human monocyte-derived macrophages.
RESULTS
We performed in vitro genome-wide loss-of-function CRISPR screens to identify the major pathways that regulate ADCP and AICP by human macrophages. Unexpectedly, we found that the classic “don’t eat me” signal CD47 has minimal impact on human macrophage phagocytosis.
By contrast, CD47 strongly suppressed mouse macrophage phagocytosis. Additionally, we identified the major histocompatibility class I complex (MHC class I) as the most potent negative regulator of ADCP.
By integrating results from the AICP and ADCP screens, we discovered that the O-linked glycosylation and sialylation pathways negatively regulate both AICP and ADCP.
CD43, a heavily sialylated cell surface glycoprotein, was the major mediator of the inhibitory effects of the O-linked glycosylation and sialylation pathways.
The inhibitory activity of CD43 was dependent on its sialic acid residues and the length of its ectodomain but independent of the canonical sialic acid–binding receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. CD43 expression reduced the avidity of interactions between immune effector cells and leukemia cells, consistent with a model where CD43 forms a steric or electrostatic glycocalyx barrier that reduces interactions with the leukemia cell surface.
We found that CD43 is overexpressed in AML patient samples, and inhibition of CD43 with antibodies enhances phagocytosis of AML cell lines and patient-derived samples.
Finally, we found that CD43 not only restrains human macrophage phagocytosis but also human natural killer (NK) and human T cell cytotoxicity.
CONCLUSION
The cell surface glycoprotein CD43 is a potent inhibitor of innate and adaptive antileukemic immunity. The inhibitory activity of CD43 on immune cells is dependent on posttranslational sialic acid modifications that are added through the O-linked glycosylation and sialylation pathways. Thus, sialylated CD43 is a potential therapeutic target for the treatment of AML."
The sialic shield of leukemia cells (Perspective, no public access)
Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity (no public access)
Genome-scale phagocytosis screens identify sialylated CD43 as a potent inhibitor of antileukemic immunity.
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