Trogocytosis contributes tumor escape and limits tumoricidal activity in hPSCs-derived CAR macrophages
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ABSTRACT:
PROVIDER: PRJNA1307401 | ENA |
REPOSITORIES: ENA
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Project description:Pluripotent stem cells (PSCs) derived chimeric antigen receptor macrophages (iCAR-Ms) hold great potential for immunotherapy, particularly against T-cell malignancies which are challenging in CAR-T therapy. Here, we generate human iCAR-Ms targeting CD5 for treating T-cell malignancies. iCAR-Ms display tumoricidal activities against various T- malignant cells expressing CD5 such as Jurkat, SUP-T1 and primary tumor cells. However, The iCAR-M tumoricidal activities are largely dependent on CD5 density on tumor cells. The escaped tumor cells show reversible CD5 loss without changes on its mRNA level. Meanwhile, the retrieved iCAR-Ms show little reduced tumoricidal activities against new tumor cells expressing CD5. Based on time lapse imaging and transcriptional analysis, we show that iCAR-Ms mainly medicate trogocytosis while less phagocytosis when approach tumor cells. Our data reveal trogocytosis as an important limitation factor in iCAR-M tumoricidal activities and tumor escape, providing a rational to develop enhanced CAR-M for immunotherapies.
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Project description:Chimeric antigen receptors (CARs) are synthetic receptors for antigen that reprogram T cell specificity, function and persistence. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies, and early trial results suggest activity in multiple myeloma. Despite high complete response rates, relapses occur in a large fraction of patients, some of which are antigen-negative and others antigen-low. Unlike mechanisms resulting in complete and permanent antigen loss, those leading to antigen-low tumour escape remain obscure. In murine leukaemia models, we show that CARs provoke reversible antigen loss through trogocytosis, an active process whereby target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide killing and exhaustion. These mechanisms affect both CD28 and 4-1BB-based CARs, albeit differentially, depending on antigen density. They can be offset by cooperative killing and combinatorial targeting.
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Project description:Cancer cells can develop an immunosuppressive tumor microenvironment to control tumor-infiltrating lymphocytes. The underlying mechanisms still remain unclear. Here, we report that mouse and human colon cancer cells acquire lymphocyte membrane proteins including cellular markers such as CD4 and CD45. We observed cell populations harboring both a tumor-specific marker and CD4 in the tumor microenvironment. Sorted cells from these populations were capable of forming organoids, identifying them as cancer cells. Live imaging analysis revealed that lymphocyte membrane proteins were transferred to cancer cells via trogocytosis. As a result of the transfer in vivo, cancer cells also acquired immune regulatory surface proteins such as CTLA4 and Tim3, which suppress activation of immune cells. RNA-sequencing analysis of ex vivo co-cultured splenocytes with trogocytic cancer cells showed reductions in Th1 activation and natural killer cell signaling pathways compared to the non-trogocytic control. Cancer cell trogocytosis was confirmed in the patient-derived xenograft models of colorectal cancer and head and neck cancer. These findings suggest that cancer cells utilize membrane proteins expressed in lymphocytes, which in turn contribute to developing the immunosuppressive tumor microenvironment.
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