Targeting Stat3 Induces Senescence in Tumor Cells and Elicits Prophylactic and Therapeutic Immune Responses against Breast Cancer Growth Mediated by NK Cells and CD4+ T Cells

Abstract

Aberrant Stat3 activation and signaling contribute to malignant transformation by promoting cell cycle progression, inhibiting apoptosis, 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-dependent C4HD cells and 4T1 cells. We immunized BALB/c mice with irradiated cancer cells previously transfected with a dominant-negative Stat3 vector (Stat3Y705F) in either a prophylactic or a therapeutic manner. Prophylactic administration of breast cancer cells transfected with Stat3Y705F (Stat3Y705F-breast cancer cells) inhibited primary tumor growth compared with administration of 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 participation of CD4+ T cells and cytotoxic NK cells. Therapeutic immunization with Stat3Y705F-breast cancer cells inhibited tumor growth, promoted tumor cell differentiation, and decreased metastasis. Furthermore, inhibition of Stat3 activation in breast cancer cells induced cellular senescence, contributing to their immunogenic phenotype. In this work, we provide preclinical proof of 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 Stat3 inactivation results in induction of a cellular senescence program disclose a potential mechanism for immunotherapy research.

A Brucella spp. Protease Inhibitor Limits Antigen Lysosomal Proteolysis, Increases Cross-Presentation, and Enhances CD8+ T Cell Responses

“…It was demonstrated by different approaches (fluorimetry, flow cytometry, and confocal microscopy) that U-Omp19 partially inhibits cathepsin L activity inside live DC lysosomes. Moreover, U-Omp19 inhibits cathepsin L activity inside live mature DCs (LPS treated), indicating that observed inhibition by U-Omp19 is not an indirect consequence of changes undertaken by DCs during maturation (29).…”

“…Three weeks later, immunized mice were injected s.c. in the right flank with 1 3 10 5 MO5 cells (B16 murine melanoma cells expressing OVA). Animals were monitored and tumor growth was measured three times a week as described previously (29).…”

Autophagy and senescence in fibrosing cholangiopathies

“…That is, exploitation of methods to evade cellular senescence and restore deregulated autophagy and inappropriate biliary innate immunity could be a promising approach for treating these intractable cholangiopathies. A therapeutic approach to these processes require a clear understanding of its regulation, particularly the signaling related to ATK/mTOR and p53 which are implicated in the process of senescence, autophagy and apoptosis [30][31][32]54,55,143,144]. Furthermore, challenges to detect differences and similarities of the disease processes in these fibrosing cholangiopathies are also informative in the evaluation of their unique pathogenesis.…”

Targeting Blockage of STAT3 in Hepatocellular Carcinoma Cells Augments NK Cell Functions via Reverse Hepatocellular Carcinoma–Induced Immune Suppression

“…It has been reported that the inactivation of STAT3 in tumor cells favored NK-cell-and T-cell-mediated antitumor immune responses (19)(20)(21); however, whether NK cell function can be augmented by blocking STAT3 in human hepatocellular carcinoma cells has not been fully investigated. In this study, we focus on NK-cell-mediated antitumor immune responses to STAT3-blocked hepatocellular carcinoma cells.…”