Sec22b-mediated cross-presentation is required for antitumor immunity and positive immunotherapy outcome

ALLOATTI, ANDRÉS

CABA

Congreso; Reunión Conjunta de Sociedades de Biociencia; 2017

CD8+ T cells mediate antigen-specific immune responses that can induce rejection of solid tumors. In this process, dendritic cells (DCs) are thought to take up tumor antigens, which are processed into peptides and loaded onto MHC-I molecules, a process called ?cross-presentation?. Neither the actual contribution of cross-presentation to anti-tumor immune responses, nor the intracellular pathways involved in vivo, are clearly established due to lack of experimental tools to manipulate this process. We aimed to develop such tools, by generating mice bearing a conditional DC-specific mutation in the sec22b gene, a critical regulator of ER-phagosome traffic required for cross-presentation in vitro. Bone Marrow DCs generated from these mice show impaired cross-presentation in vitro, but unaltered antigen presentation by the classical MHC-I and MHC-II pathways. In addition, the cross-presentation capacity of DCs isolated from spleen is reduced ex vivo and, as a consequence, defective cross-priming of CD8+ T cell responses in vivo is evident when immunizing with dying cells. These mice are also defective for anti-EG7 tumor immune responses, and resistant to treatment with anti-PD-1 when using the tumor cell line MCA101. Moreover, CD8+ T cells are equally functional in wild-type and silenced mice. These findings suggest that Sec22b-dependent cross-presentation in DCs is required to initiate CD8+ T cell responses to dead cells and to induce effective anti-tumor immune responses during anti-PD-1 treatment in mice.