LEUKOCYTE-SPECIFIC PROTEIN 1 ABSENCE REDUCES CYTOTOXIC RESPONSE GENERATION BY AFFECTING DENDRITIC CELLS AND CD8+ T CELL FUNCTION

MARÍA MERCEDES PASCUAL; NICOLÁS DANIEL DHO; CONTANZA MARIN ; MARÍA INÉS CRESPO; MARÍA CRISTINA PISTORESI; BELKYS MALETTO; GABRIEL MORÓN

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

SAI - SAIC - SAFIS

LSP1 is an intracellular F-actin binding phosphoprotein expressed in leukocytes and endothelial cells from humans and mice. LSP1 polymorphisms or reduced expression are risk factors for some types of cancer. We demonstrated that B16-OVA tumors in LSP1 KO mice reach bigger sizes and grow faster than in wild type (WT) mice. Also, there is a reduced extravasation efficiency of LSP1 KO leukocytes into tumors harvested from WT and LSP1 KO mice. In dendritic cells (DCs), capture of tumoral antigen and its transport to draining lymph node (dLN) is affected by LSP1 absence. In addition, LSP1 KO DCs cannot activate and induce CD8+ T cell proliferation in an appropriate way.Taking into account these previous results, we aimed to investigate if intratumoral CD8+ T cell functionality is affected by LSP1 absence. We observed a reduced frequency of CD8+ T cell producing perforin and granzyme B in LSP1 KO tumors (p<0.01), as well as a reduced frequency of polyfunctional CD8+ T cell producing Lamp1 e IFN-γ simultaneously (p<0.05). To evaluate the impact of the reduced production of effector molecules in CD8+ T cell-mediated cytotoxicity, WT and LSP1 KO mice were immunized with OVA adjuvanted in CpG-CoA-ASC16 and after 7 days an in vivo CTL assay was performed. A lower lysis percentage was observed in LSP1 KO mice with respect to WT mice (p<0.001). To investigate the impact of the reduced cytotoxic function in tumor development, WT and LSP1 KO mice immunized as indicated above were inoculated with 1.105 B16-OVA cells and tumor size was followed up. Immunization reduced the tumor size in WT (p<0.001) and LSP1 KO mice (p<0.01). However, tumors in immunized LSP1 KO mice grew still bigger than in immunized WT mice. Immunization also improved mice survival in both animal groups (p<0.01). These results demonstrate that LSP1 absence reduces CTL response generation through affecting DCs and CD8+ T cell function and therefore tumor control development is impaired.