Immunotherapy against Breast Cancer Based on Cellular Senescence Induced by Targeting Stat3

SCHILLACI, ROXANA

Los Cocos, Cordoba

Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Aberrant Stat3 activation and signaling contribute to malignant transformation by promoting cell cycle progression, inhibitingapoptosis, and mediating tumor immune evasion. Stat3 inhibition in tumor cells induces the expression of chemokines and proinflammatory cytokines, so we proposed to apply Stat3-inhibited breast cancer cells as a source of immunogens to induce an antitumor immune response. Studies were performed in two murine breast cancer models in which Stat3 is activated: progestin-dependentC4HD cells and 4T1 cells.We immunized BALB/c mice with irradiated cancer cells previously transfected with a dominant-negativeStat3 vector (Stat3Y705F) in either a prophylactic or a therapeutic manner. Prophylactic administration of breast cancer cellstransfected with Stat3Y705F (Stat3Y705F-breast cancer cells) inhibited primary tumor growth compared with administrationof empty vector-transfected cells in both models. In the 4T1 model, 50% of the challenged mice were tumor free, and the incidence of metastasis decreased by 90%. In vivo assays of C4HD tumors showed that the antitumor immune response involves the participationof CD4+ T cells andcytotoxic NK cells. Therapeutic immunization with Stat3Y705F-breast cancer cells inhibited tumorgrowth, promoted tumor cell differentiation, and decreased metastasis. Furthermore, inhibition of Stat3 activation in breastcancer cells induced cellular senescence, contributing to their immunogenic phenotype. In this work, we provide preclinical proofof concept that ablating Stat3 signaling in breast cancer cells results in an effective immunotherapy against breast cancer growth and metastasis. Moreover, our findings showing that inactivation of the oncogene Stat3 induces a senescence programdisclose a potential mechanism for immunotherapy research.