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.

An immune relevant signature for predicting prognoses and immunotherapeutic responses in patients with muscle‐invasive bladder cancer (MIBC)

“…Several studies have observed that some of these genes play important roles in the regulation of the immune response. For example, CIITA can trigger antitumor immunity by inducing the expression of the MHC class II molecules of tumor cells, CD3D can regulate the proliferation and development of T cells, and GNLY can encode granulysin, which can cause the lysis of tumor cells . Interestingly, using the median TIM score as a cutoff value, we observed that the genes of patients with high TIM scores were enriched in protumor pathways and that the genes of patients with low TIM scores were enriched in inflammatory pathways.…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…Adoptive transfer methods are based on patientderived lymphocytes that are expanded, genetically modified, or activated ex vivo before being reinfused (Robbins et al, 2015;Lu et al, 2017). In addition, the application of antitumor vaccination approaches have made considerable progress in recent years (reviewed in Rammensee and Singh-Jasuja, 2013;Accolla et al, 2019;Peng et al, 2019). The method most widely established in the clinic is the treatment with checkpoint inhibitors.…”

Development of a Multi-gene-based Immune Prognostic Signature in Ovarian Cancer

“…The most critical TFs were CIITA, BATF, VDR, and CBX2. Among them, CIITA has been shown to drive MHC Class II expressing tumor cells as professional antigen presenting cell (APC) performers, thus activating the immune cells and constructing the speci c optimal anti-tumor vaccine [13]. BATF can induce the T cell exhaustion during chronic infection, which is characterized by expression of inhibitory receptors and protect cells from excessive immunopathology [14,15].…”