CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine

Abstract

Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor adaptive immune response as they recognize antigens presented on MHC class I (MHC-I) molecules usually expressed in all cells and thus also in tumors. However, attempts to translate in clinics vaccination protocols based only on tumor-specific MHC-I-bound peptides have resulted in very limited, if any, success. We believe failure was mostly due to inadequate triggering of the TH arm of adaptive immunity, as TH cells are necessary to trigger and maintain the proliferation of all the immune effector cells required to eliminate tumor cells. In this review, we focus on a novel strategy of anti-tumor vaccination established in our laboratory and based on the persistent expression of MHC class II (MHC-II) molecules in tumor cells. MHC-II are the restricting elements of TH recognition. They are usually not expressed in solid tumors. By genetically modifying tumor cells of distinct histological origin with the MHC-II transactivator CIITA, the physiological controller of MHC-II gene expression discovered in our laboratory, stable expression of all MHC class II genes was obtained. This resulted in tumor rejection or strong retardation of tumor growth in vivo in mice, mediated primarily by tumor-specific TH cells as assessed by both depletion and adoptive cell transfer experiments. Importantly these findings led us to apply this methodology to human settings for the purification of MHC-II-bound tumor specific peptides directly from tumor cells, specifically from hepatocarcinomas, and the construction of a multi-peptide (MHC-II and MHC-I specific) immunotherapeutic vaccine. Additionally, our approach unveiled a noticeable exception to the dogma that dendritic cells are the sole professional antigen presenting cells (APC) capable to prime naïve TH cells, because CIITA-dependent MHC-II expressing tumor cells could also perform this function. Thus, our approach has served not only to select the most appropriate tumor specific peptides to activate the key lymphocytes triggering the anti-tumor effector functions but also to increase our knowledge of intimate mechanisms governing basic immunological processes.

Keywords: APC; CD4+ TH cells; CIITA; MHC-II; tumor vaccines.

Figure 1

Expression of CIITA-driven MHC-II expression in tumor cells drastically modify the histology of the tumor microenvironment. MHC class II negative mouse tumors of distinct histologic origin and H-2 genotype (left side) are very little infiltrated by blood-derived cells (cold or non-inflamed tumor). In the mouse tumor models analyzed in our studies, scarce infiltration of neutrophils and monocyte-macrophages was detected in vivo in the microenvironment of parental tumors. Upon stable transfection with CIITA and consequent expression of MHC class II molecule, tumors became rapidly infiltrated by CD4+ T cells, followed by CD8+ T cells and only later by dendritic cells and macrophages (inflamed or hot tumor). As result of the intense lymphocyte infiltration, large areas of tumor necrosis were generated. Thus, the tumor microenvironment was drastically modified by the CIITA-driven MHC class II expression in the tumor cells.

Figure 2

Tumor cells expressing CIITA-driven MHC-II molecules are potent surrogate APC to prime relevant tumor-specific TH cells. The MHC class II-bound tumor peptidome (Tumap, red symbols) derived from CIITA-driven MHC-II expressing cells is highly enriched of tumor-specific epitopes (Lower part) as compared to the one of classical APC, such as dendritic cells (DC), that may capture tumor antigens (TA) only after phagocytosis of dying MHC-II-negative tumor cell debris (Upper part). As a result, in CIITA-tumors, MHC-II-tumor peptide complexes efficiently stimulate and amplify higher number of tumor-specific TH cell clones (in red) to generate a strong immune response capable to reject the tumor (Lower part). On the contrary, classical APC do not efficiently select sufficient tumor-specific peptides from MHC-II-negative tumor cells to be presented within the context of their MHC-II. As a consequence DC cannot efficiently prime tumor-specific TH cell clones and tumor takes off and grows (Upper part).