Defense from infection or cancer is provided by coordinated actions of the innate and adaptive immune system, including B lymphocytes that generate antibodies (Abs) against pathogens or tumor antigens. B cells establish immune synapses with antigen-presenting cells during activation to initiate Ab-production, which may include entrance into a germinal center (GC) reaction to generate very high-affinity Abs. Establishment of an immune synapse requires polarity proteins to coordinate uptake and processing of external antigens. For this, there is a highly conserved family of partitioning defective (Par) proteins that mediates cell polarity in multiple cell types. In particular, Par-3, a member of the Par polarity complex (Par-3, aPKC, Par-6), is a key protein that localizes to the immune synapse and is required for B cell polarization and immune synapse formation. Recently, we showed that LKB1, the mammalian homolog of Par-4 and a regulator of energy metabolism, controls B cell activation, GC formation and differentiation into Ab-producing plasma cells. However, roles for LKB1 in B cell polarity, immune synapse formation and anti-tumor immunity are unknown. Based on previous studies showing that LKB1 induces cell polarity and co-localizes with Par-3, we hypothesize that LKB1 is required for Par complex assembly and controls immune synapse formation during B cell activation. Subcellular analysis of LKB1 by immunofluorescence microscopy in mouse primary B cells reveals LKB1 co-localization with aPKC in membrane protrusions required for immune synapse formation. Interestingly, B cell specific LKB1 knock out (BKO) mice exhibit mislocalization of aPKC/Par complex, loss of lymphoid tissue polarity and spontaneous B cell activation that results in the formation of giant GCs and secretion of proinflammatory cytokines and chemokines. Similar inflammatory profiles with T cell chemoattractants are known to recruit CD8+ cytotoxic T lymphocytes (CTLs) into solid tumors, such as melanoma. These similarities suggest that LKB1 inactivated B cells in the tumor microenvironment could stimulate T cell infiltrates into solid tumors. Our studies suggest that physiologic inactivation of LKB1 in B cells controls B cell activation, GC formation and potentially infiltration of T cells in the tumor microenvironment during anti-tumor responses. We are currently utilizing an exciting genetic mouse melanoma model to examine the role of LKB1 in promoting anti-tumor immunity. Together, our studies assess LKB1 as a target for augmenting adaptive immunity against cancer.
Citation Format: Laura Jimenez, Lynnea Waters, Diane N.H. Kim, Nicole Walsh, Michael A. Teitell. Roles for LKB1 at the immune synapse during B-cell activation and antitumor responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B46.