Abstract
Simple SummaryIt 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.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.
Highlights
The immune response against cancer, or better against cancers, is a complex series of events that are regulated by both intrinsic and extrinsic mechanisms, whose final goal should be the elimination of the tumor cells or at least the control of their growth [1]
While structural mutations and/or disregulations of gene expression that are at the basis of oncogenesis should contribute to create neo-antigens or overexpressed cellular proteins that are recognizable by the immune system, in the same time they might affect genes that are strongly involved in antigen presentation such as major histocompatibility complex (MHC) molecules, in particular, MHC class I
We have extensively reviewed our approach aimed at rendering tumor cells constitutively positive for MHC class II expression by the genetic transfer of the MHC class II
Summary
The immune response against cancer, or better against cancers, is a complex series of events that are regulated by both intrinsic and extrinsic mechanisms, whose final goal should be the elimination of the tumor cells or at least the control of their growth [1]. While structural mutations and/or disregulations of gene expression that are at the basis of oncogenesis should contribute to create neo-antigens or overexpressed cellular proteins that are recognizable by the immune system, in the same time they might affect genes that are strongly involved in antigen presentation such as major histocompatibility complex (MHC) molecules, in particular, MHC class I (MHC-I) molecules [6] These molecules, designated HLA-A, -B, -C in human, are normally expressed in all cell types. At variance with MHC-I, loading of peptides on MHC-II molecules preferentially takes place in acidic endosomal compartments [14], where degraded products from endocytosed external materials are concentrated and where MHC-II molecules, complexed with the invariant (In) chain, a molecule that prevents premature peptide loading in endoplasmic reticulum, are routed after biosynthesis [15,16] Because of these features, it is widely assumed that MHC-II molecules cannot present peptides derived from the processing of endogenously synthesized molecules. We investigated whether tumor cells may act as surrogate APC of their own tumor antigens, provided that they could be modified to express MHC-II molecules in a “physiological” modality
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