Abstract 2883: Improved generation of central memory CD8+ T cells with CD40L expressing recombinant vaccinia virus

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.2883-2883
• Main Authors: Trella, Emanuele, Panoupolos, Evangelos, Heidtmann, Swantje, Raafat, Nermin, Spagnoli, Giulio Cesare, Zajac, Paul
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-2883

Immunological memory is the ability of the immune system, upon re-encounter with the same antigen, to respond with greater speed and intensity and constitutes the basis for vaccination. Regarding CD8+ T-cells, the memory compartment has been divided in different subsets of memory cells: Central Memory CD8+ T cells (CD45RO+CD62L+; Tcm) and Effector Memory CD8+ T cells (CD45RO+CD62L- ; Tem). In cancer immunotherapy, studies performed on animal models showed that Tcm tumor-reactive CD8+ T cells, as compared to effector memory T cells, confer superior antitumor immunity leading to better outcome.. In the last decades has been clarified that CD4+T cells help, during CD8+ T cells memory differentiation, is mainly mediated by the CD40L expression on their surface upon activation and consecutive triggering of CD40 expressed by antigen presenting cells and activated CD8+ T cells. Recombinant vaccinia virus (rVV) is one of the most immunogenic viral vectors enabling specific targeting and modulation of anti-tumor immune responses. We previously demonstrated that infection of antigen presenting cells (APCs) , with a non-replicating rVV encoding human CD40L (rVV-CD40L) was leading to an efficient licensing of APC, as demonstrated by increased expression of surface ligand/receptors (MHC I/II, CD80 and CD86),Th1 and homeostatic cytokines (IL-12, TNFa, IL-7 and IL-15). Using sorted naive CD8+ Tcells (CD45RA+CD62L+) primed with infected allogeneic CD14+ we observed that activated cells had an increased central memory phenotype (CD45RO+ CD62L+) with rVV40L infection as compared to culture primed with wild type virus infected CD14+ cells or treated with soluble 40 Ligand recombinant protein (s40L). The majority of Tcm express even the a-chain of IL-7 receptor (IL-7Ra) which has been reported to be express on “Bona Fide” memory cells and is associated with an increased cells survival. In an autologous system targeting a tumor antigen response, we demonstrated how CD14+rVV40L, as compared controls or soluble 40L stimulation, strongly promote the expansion of MelanA/Mart-1 specific CD8+ characterized with a Tcm phenotype and expression of IL-7Ra. Functional characterization of these tumor specific CD8+ demonstrated higher levels of IFN-g and IL-2. Studies performed in murine models have shown that, upon activation, CD8+ T cells can also express the CD40 receptor and therefore become directly sensitive to CD40L activation. However,in our hands, induction and characterization of