How AML Leukemia Cells Use a “Sugar Coat” to Hide from the Immune System, CRISPR Screen Finds

Research Summary

Study Title: Sialylated CD43 forms a glyco-immune barrier that restrains anti-leukemic immunity

Publication: Science

Corresponding Dana-Farber Cancer Institute authors: Todd Golub, MD, Mounica Vallurupalli, MD

Summary: Dana-Farber Cancer Institute researchers, in collaboration with the Broad Institute and Mass General Brigham, used a genome-wide CRISPR knockout screen, a method that turns off genes one at a time, to pinpoint which genes help human AML leukemia cells avoid being engulfed, or eaten, by immune cells called macrophages. They ran the screen in a human system, growing human AML cells together with human macrophages.

One important result involved CD47, a well-known “do not eat me” signal. CD47 strongly reduced phagocytosis by mouse macrophages, but in this study, it only weakly suppressed phagocytosis by human macrophages. This species difference suggests that results from mouse models may overstate how much CD47 drives immune evasion in human AML, which could help explain why some macrophage boosting approaches targeting CD47 have not improved outcomes in patients.

Instead, the genes that most strongly helped AML cells avoid immune attack were involved in adding certain sugars to proteins on the cell surface, called O linked glycosylation and sialylation. The researchers found that one sugar coated surface protein, called CD43, was the main driver of this effect in AML cells.

CD43 blocked macrophages from engulfing leukemia cells because of the size and length of the part of the protein that sticks out from the cell surface, acting like a physical barrier. This effect did not depend on several known macrophage receptors that detect sialic acid sugars, called SIGLEC 1, SIGLEC 7, and SIGLEC 9. CD43 also made it harder for other immune cells, including natural killer cells and T cells, to attack AML, suggesting it can shield leukemia cells from multiple parts of the immune system.

Significance: AML remains difficult to treat with immunotherapy, and approaches meant to help macrophages eat leukemia cells have not led to clear benefits for patients. This study suggests that, in human AML, leukemia cells may escape the immune system less through classic “do not eat me” signals and more through a sugar-coated barrier on the cell surface, driven by CD43 and O linked glycosylation.

These results point to CD43, and the genes that add and maintain its sugar coating, as possible new targets to help make AML cells easier for the immune system to attack, including macrophages, natural killer cells, and T cells. Future research will need to determine how CD43 and its sugar modifications differ between leukemia cells and normal cells, and to identify safe and effective ways to weaken this protective barrier.

Funding: National Institutes of Health grant R35 CA242457, Calico Life Sciences LLC, National Institutes of Health grant T32 CA009172-46, Jonathan Kraft Translational Team Research Award, National Institutes of Health grant T32HL116324-07, Damon Runyon Cancer Research Foundation, Edward P. Evans Foundation.