Adequate Antigen Availability (AAA) in antitumor immunity: Definition and consequences for novel strategies of tumor prevention and antitumor treatment

Present immunopreventive and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus, newly conceived anti-tumor strategies of intervention are urgently needed. Here we introduce the concept of Adequate Antigen Availability (AAA) defined as the optimal tumor antigen dose and related antigen processing and MHC class II-restricted presentation necessary to trigger efficient tumor-specific TH cells (1). We will present results on a preventive anti-tumor vaccination system that consists in injecting tumor cells genetically modified to constitutively express MHC class II molecules by transfecting the MHC-II transcriptional activator CIITA. AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific CD4+ TH cells. We will show that tumor rejection against the CIITA-transfected neoplastic cells is brought about by the generation of persistent anti-tumor TH cell memory, responsible of protecting the animals from subsequent challenges with parental, untransfected tumor cells. This approach has been validated in tumor cells of different histotypic origin and of distinct MHC genotype (H-2d and H-2b). Importantly, the anti-tumor TH cell response modifies the tumor microenvironment, favouring the infiltration of CD4+ TH cells, CD8+ cytolytic T cells and granulocytes and dramatically reducing both intratumoral and lymphnode infiltration of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Thus the optimal initiation of the adaptive immune response, dictated by AAA, is sufficient to reorient the tumor microenvironment from a pro-tumor to an anti-tumor microenvironment. Our approach is, at present, applied to human clinical setting in hepatocellular carcinomas (2) whereby human tumor cells are rendered HLA class II-positive by CIITA genetic transfer with the aim to purify and sequence immunogenically relevant HLA class II-bound tumor–associated antigenic (TAA) peptides. In conjunction with similarly derived HLA class I-restricted TAA peptides, they will be the basis for the construction of a multi-peptide, multi-epitope vaccine that can target both CD4+ TH and CD8+ CTL anti-tumor responses.