Systemic BCG administration stimulates NK and T cell-mediated antitumor lung immunity and overcomes tumor resistance to immune checkpoint inhibition

Abstract

Intravesical administration of BCG was the first immunotherapy approved by the FDA and it is still nowadays the treatment of choice for a subset of non-muscle invasive bladder cancer patients. Considering this precedent and the strong capabilities of BCG to trigger cellular responses, we hypothesized that systemic administration of BCG by the intravenous route (IV BCG), a vaccination strategy that has been found well-tolerated, highly immunogenic and effective at preventing tuberculosis infection in non-human primates, could result effective against lung tumors. Our data revealed that IV BCG, administered in a therapeutic scenario, slowed tumor growth and extended mouse survival in models of B16-F10 lung metastasis and in an orthotopic LLC lung cancer model, by enhancing both antitumoral innate and adaptive immune responses. IV BCG administration induced tumor-specific CD8+ T cell responses with enhanced cytotoxic function, in a process dependent on conventional type 1 Dendritic Cells (cDC1s). In addition, we found that BCG strongly activated both human and mouse NK cells. Remarkably, NK cell depletion prevented BCG-induced cDC1 recruitment to the tumor-bearing lung and reduced cDC1 upload with tumor-derived antigens, as well as the subsequent induction of tumor-specific CD8+ T cell responses and tumor control. Of note, IV BCG strongly synergized with the immune checkpoint inhibitor (ICI) anti-PD-L1 in lung tumors which were otherwise resistant to immune checkpoint blockade given as monotherapy, suggesting the IV BCG could represent a promising ICI-resensitizing cancer immunotherapy.