Session III: Involvement of HLA-class II molecules in tumor rejection - The role of epitopes for tumor-reactive T cells

There is little doubt that CD4 ⁺ helper T lymphocytes (HTL) play an important role in the establishment of effective antitumor immunity. During the induction phase of T cell-mediated immune responses, HTL participate in the induction of antigen-specific CD8 ⁺ cytotoxic T lymphocytes (CTL), which are the main effector immune cells against malignant cells. In addition, HTL may also be important in the maintenance of long-lived CTL responses, which is critical for the prevention of relapses and in the maintenance of immune memory. In addition, CD4 ⁺ HTL are capable of exhibiting antitumor effector function by directly recognizing and killing MHC class II ⁺ tumor cells that present HTL epitopes on their surface. For all the above reasons, the inclusion of both CTL and HTL epitopes in antitumor vaccines should be seriously considered in order to maximize the possibility of attaining optimal therapeutic effectiveness. Numerous MHC class I epitopes from tumor-associated antigens (TAA) such as HER2, CEA, MAGE and several laboratories have identified gp100 over the past 10 years. On the other hand, few MHC class II epitopes for these TAA have been defined. In our laboratory the focus has been on the identification of MHC class II-restricted epitopes using two approaches: (1) reverse immunology (predictive approach) and (2) a combined genetic/proteomic approach using tumor-reactive HTL. We will present a summary of our most recent results analyzing the strengths and weaknesses of these methods and discuss how we plan to take this knowledge into the clinic.