New research into membrane dynamics reveals how lipids derived from cancer cells can skew macrophages towards an immunosuppressive phenotype, via a manipulation of the lipid composition within the ER membrane.
Upon recognition of beta-glucosylceramide released by cancer cells, macrophages increase the cholesterol synthesis and reshuffle the lipidic composition of the endoplasmic reticulum (ER) membrane that results in activation of ER stress response and immunosuppressive phenotype.
Research* undertaken by Giusy Di Conza, postdoctoral researcher in the Ho Lab, part of the Ludwig Lausanne branch, demonstrates that interfering with the production of beta-glucosylceramide in cancer cells, inhibiting ER stress response in macrophages, or manipulating the lipid pathway of the ER membrane, are all effective approaches that reduce tumor burden and survival of suppressive macrophages.
The results, published in Nature Immunology, open a new field of research on the role of membrane dynamics within cells that are present in the tumor microenvironment and highlight the importance of targeting ceramide metabolism in cancer. They also support the use of LXR agonist for cancer treatment, currently undergoing clinical evaluation.
*Tumor-induced reshuffling of lipid composition on the ER membrane sustains macrophage survival and pro-tumorigenic activity.