New strategies of mammary cancer vaccination.

A new strategy of vaccination against mammary tumors, extendible to tumors of distinct histological origin, based on the administration of tumor cells genetically modified to express major histocompatibility complex (MHC) class II gene products, will be described. Expression of MHC class II molecules in solid tumors, generally lacking these molecules, is achieved by transfecting tumor cells with the MHC class II transactivator (CIITA), the major regulator of the entire family of MHC class II genes. CIITA is encoded by the AIR-1 locus, discovered in our laboratory. The rationale underlying this approach consists in making the tumor cells a sort of surrogate antigen presenting cells for MHC-II-restricted CD4 + T helper (TH) cells. Indeed, it is known that an efficient adaptive immune response against cancer cells can only be achieved if tumor-specific TH cells, the key lymphocyte subpopulation required to trigger both humoral and cellular effector mechanisms, are optimally stimulated. Results from our group show that: (a) CIITA-modified tumor cells can be rejected in vivo by syngeneic immunocompetent mice; (b) this rejection is mediated primarily by CD4 + TH lymphocytes that activate cytolytic CD8 + T cell effectors ; (c) tumor-rejecting mice are resistant to challenge with parental unmodified tumor cells and display long term immune memory; (d) anti-tumor vaccination can be reproduced by using inactivated, nonreplicating CIITA-transfected tumor cells; (e) immune effectors and particularly primed CD4 + TH cells can be used successfully in approaches of immunotherapy of established tumors. These results open the way to envisage a possible use of CIITA-modified mammary tumor cells as a vaccine for increasing both the inducing and the effector phase of the anti-tumor immune response in human settings.