Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer

Abstract

Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.

Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

“…Although the exact molecular mechanism is not elucidated, the increased number of MAITs was CAST chromosome ( Figure 2E) and hematopoietic ( Figure 2B) intrinsic and was already observed in the thymus conventional T cell accumulation or survival. Therefore, this model will be very useful to study, for instance, the mechanisms of bacillus Calmette-Guérin (BCG) antitumor activity during the treatment of bladder carcinoma (57). This MAIT-rich mouse model will also allow the test of MAIT stimulation with synthetic ligand as a therapeutic tool in various diseases or as an adjuvant for vaccine development.…”

“…Mononuclear cells were recovered from the interface. Intestinal lymphocytes were isolated as previously described (20,57,58). Briefly, large intestines were collected in cold PBS.…”

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

“…49,50 This treatment is particularly efficient when pre-existing BCG-specific T cells are primed for interferon g production, presumably within residual tumor lesions or draining lymph nodes. 51 In this context, the urinary concentration of CXCL8 has turned out to constitute an early biomarker of subsequent immune responses and to predict therapeutic outcome. 52 BCG induces the apoptotic death of bladder cancer cells either directly or through the activation of humoral or cellular immune effectors, 53 suggesting that, by promoting ICD, CXCL8 might have a decisive role in the therapeutic efficacy of BCG-based immunotherapy.…”

Mycobacteria-Derived Agents for the Treatment of Urological and Renal Cancers

“…In summary, BCG firstly interacts with remaining bladder tumor cells inducing apoptosis and/or cell cycle arrest as demonstrated in in vitro experiments [24][25][26]. Moreover, internalization of the mycobacteria triggers the production of cytokines and chemokines [27] that work as initial signals for the host immune system, leading to the infiltration of multiple immune cells into the bladder lumen, as observed in in vivo models of the disease [28,29] as well as in BCG-treated patients [27]. Although the role of each infiltrated immune subsets-T cells, B cells, natural killer (NK) cells, macrophages, γδ cells, etc.-is still unknown, their presence is critical for an appropriate antitumor response [30].…”