Lymph node‐induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin‐1

Summary Emerging evidence indicates that the tumour microenvironment ( TME ) regulates the behaviour of chronic lymphocytic leukaemia ( CLL ). However, the precise mechanism and molecules involved in this process remain unknown. Gene expression profiles of CLL cells from lymph node ( LN ), bone marrow ( BM ) and peripheral blood ( PB ) indicate overexpression of a tolerogenic signature in CLL cells in lymph nodes ( LN ‐ CLL ). Based on their role in B cell biology, the progression of CLL , or immune regulation, a few genes of this 83‐gene signature were selected for further analyses. We observed a significant correlation between the clinical outcomes and the expression of CAV 1 ( P  = 0·041), FGFR 1 isoform 8 ( P  = 0·032), PTPN 6 ( P  = 0·031) and ZWINT ( P  < 0·001). CAV 1, a molecule involved in the regulation of tumour progression in other cancers, was seven‐fold higher in LN ‐ CLL cells compared to BM ‐ and PB ‐ CLL cells. Knockdown of CAV 1 expression in CLL cells resulted in significantly decreased migration ( P  = 0·016) and proliferation ( P  = 0·04). When CAV 1 was knocked down in B and T cell lines, we observed an inability to form immune synapses. Furthermore, CAV 1 knockdown in CLL cells impaired their ability to form immune synapses with autologous T lymphocytes and allogeneic, healthy T cells. Subsequent analyses of microarray data showed differential expression of cytoskeletal genes, specifically those involved in actin polymerization. Therefore, we report a novel role for CAV 1 in tumour‐induced immunosuppression during the progression of CLL .