LAUSR

Simple Summary It is becoming clear that combined approaches are required to fight and succeed against cancer. As far as immune-based strategies, new generation anti-tumor vaccines will certainly play a crucial role. A key aspect is to identify tumor antigens which optimally stimulate CD4+ T helper cells, as these cells are crucial to triggering and maintaining all effector mechanisms of the adaptive immune response. Our approach is to render tumor cells surrogate antigen presenting cells for their own tumor antigen by forcing them to express de novo MHC class II molecules after the genetic transfer of CIITA, the major transcriptional controller of MHC class II gene expression. The unprecedented strong stimulation of tumor-specific CD4+ T cells that were obtained with our approach let us hope that this will help in identifying a constellation of MHC class II-restricted tumor antigens for more potent next generation anti-tumor vaccines. Abstract Despite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types of tumors. Within this frame, novel vaccination strategies that are based on optimal stimulation of the key cell governing adaptive immunity, the CD4+ T helper cell, will certainly help in constructing more efficient treatments. In this review, we will focus on this aspect, mainly describing our past and recent contributions that, starting with a rather unorthodox approach, have ended up with the proposition of a new idea for making available an unprecedented extended repertoire of tumor antigens, both in quantitative and qualitative terms, to tumor-specific CD4+ T helper cells. Our approach is based on rendering the very same tumor cells antigen presenting cells for their own tumor antigens by gene transfer of CIITA, the major transcriptional coordinator of MHC class II expression discovered in our laboratory. CIITA-driven MHC class II-expressing tumor cells optimally stimulate in vivo tumor specific MHC class II-restricted CD4 T cells generating specific and long lasting protective immunity against the tumor. We will discuss the mechanism underlying protection and elaborate not only on the applicability of this approach for novel vaccination strategies amenable to clinical setting, but also on the consequence of our discoveries on sedimented immunological dogmas that are related to antigen presentation.