Genetic approaches for the induction of a CD4⁺ T cell response in cancer immunotherapy

Abstract

Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-gamma-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development.

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

“…The transfection of DCs with sig-MelanA-LAMP1, sig-MAGE-LAMP1 and sig-carcinoembryonic antigen (CEA)-LAMP1 mRNA encoding chimeric MART1, MAGE and CEA have been shown to promote induction of an antigen-specific CD4 þ T-cell response. [53][54][55] The vaccination of mice with DNA encoding sig-E7-LAMP1-16 have generated simultaneous CD4 þ and CD8 þ T-cell responses against the human papillomavirus. [56][57][58] Lastly, the injection of DCs transfected with the telomerase reverse transcriptase-LAMP1 mRNA has led to an enhancement of antigen-specific CD4 þ and CD8 þ T cells against metastatic prostate cancer in humans.…”

Characterization of a Permissive Epitope Insertion Site in Adenovirus Hexon

“…Epitopebased vaccines have been developed for a number of infectious agents, including human papillomavirus, hepatitis B virus, and human immunodeficiency virus, some of which have shown great promise in protecting against disease in animal models (16,31,34,44). In addition, the identification of epitopes that are overexpressed or present only on cancer cells has led to the development of epitope-based cancer vaccines (8). One area in which this approach has given encouraging results is in the treatment of HER-2/neu-positive breast cancers, since the HER-2/neu protein is highly overexpressed on cancer cells (53).…”

Dendritic Cell Immune Therapy to Break or Induce Tolerance

“…Overall, results showed the potential ability of DCs transduced with LV encoding for TAAs to generate tumor-specific CD4 + and CD8 + T cells [98]. CD8 + T cells play a major role in cancer eradication [104]; however, CD4 + T cell response is crucial for sustaining CTL effector functions and for inducing a memory response in vivo [105,106]. Priming of CD4 + T cells by LVtransduced DCs occurs only if the LV-encoded Ag has access to an MHC class II presentation pathway.…”