EFFECT OF egc SUPERANTIGENS ON MALIGNANT B AND T CELLS. RATIONALE FOR COMBINATION WITH CURRENT ANTITUMOR THERAPIES

VERGARA-RUBIO M ; REDOLFI D.; SARRATEA MB; VILA C; IANNANTUONO LÓPEZ L; NOLI TRUANT S.; MALUSARDI C; CORDINI G; MALCHIODI ; LOMPARDÍA SL; FERNÁNDEZ MM

Congreso; Reunión Anual de la Sociedad Argentina de Inmunología; 2023

SAI

Lymphomas/leukemias are prevalent T and B-cell hematologic malignancies.Conventional treatment, encompassing radiotherapy and chemotherapy, not only yieldslimited tumor-specific outcomes but also incurs significant adverse effects. Thus,targeted therapies with less toxicity are essential. Immunotherapy's rise inoncohematological care and monoclonal antibody integration into therapeutic strategiesunderscore the need for tumor-exclusive antigens, as most antibodies currently targetshared antigens in normal tissues. On the other hand, strategies that attempt to inducea host immune response to the tumor require adequate immunogenicity of theneoplastic cells. Patients are often immunocompromised. In contrast to conventionalantigens, superantigens (SAgs) are viral or bacterial proteins that interact withconventional targets such as the constant region of the T-cell antigen receptor (TCR)and different regions of MHC-II. The aim of this study was to investigate the effects of TSAgs on Hodgkin and non-Hodgkin lymphomas and human acute leukemia (ALL) celllines. Additionally, we aimed to assess the extent of these effects in combination withlow doses of Vincristine (VCR), a vinca alkaloid primarily used as a chemotherapeuticagent with well-described toxicity. We observed an increase in the expression of lateactivation markers (CD86) on the surface of malignant B cells, as measured by flowcytometry, after 48 hours of treatment with egc operon SAgs (SEG and SEI) at10µg/mL. At 72 and 96 hours, we found a decrease in metabolic activity using the XTTassay for all B cell lines treated with 100µg/mL of SAgs (p<0.0001, Dunnett's multiplecomparisons test), including the Hodgkin lymphoma KM-H2 cell line. Apoptosis at thesame SAg concentration was determined by Annexin V-PE/7-AAD staining at these timepoints. Furthermore, we tested different concentrations of VCR and confirmed its dose-dependent induction of cell death at 48, 72, and 96 hours. We tested an effectiveconcentration of SAgs with the lowest and least toxic concentrations of the vincaalkaloid [<1µM] to determine if it could enhance the effect on metabolic activity orsurvival. After 96 hours, the combined treatment of VCR [0.001µM] and 100µg/mL SEIled to a potentiated decrease in Burkitt's lymphoma proliferation, indirectly assessedthrough the XTT assay (p<0.0001). Jurkat cells express a TCR that is non-reactive toegc SAgs; however, the effect of these SAgs on T lymphocyte survival was evident at24 hours and at much lower concentrations (SEG and SEI at 1µg/mL). For this purpose,the Jurkat cell line was co-cultured with THP-1 cells or plaque-attached monocytes asantigen-presenting cells (APCs). These results strongly suggest that SAgs T caninteract with other non-conventional receptors on the target cells, promoting death afteractivation.