Immune responses to human tumors: development of tumor vaccines

CD Platsoucas PhD^a, J Pappas^a, M Heckel^a, W-J Jung^a, JE Fincke^a, CD Katsetos^a,b, R Schwarting^c, RS Freedman^d

^aDepartment of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States, ^bDepartment of Pediatrics, Section of Neurology, Drexel University College of Medicine, Philadelphia, PA, United States, ^cDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson Medical College, Philadelphia, PA, United States, ^dDepartment of Gynecologic Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States

AIM: Human and animal tumor cells are recognized in many cases as non-self by the cells of the immune system and elicit an immune responses that may result in their elimination. Three major lines of evidence have demonstrated the presence of antitumor responses in humans: (i) the development in rIL-2 of T-cell lines/ clones with cytolytic activity and/or cytokine production primarily against autologous tumor cells, or tumor cells expressing identical peptide/MHC epitopes; (ii) the presence of monoclonal/ oligoclonal T cells in human tumors; (iii) the identification and molecular cloning and expression of human tumor antigens. Structurally defined tumor antigens are available now for the development of tumor vaccines. Peptides derived from these tumor antigens elicit HLA-restricted immune responses, permitting the development of peptide or recombinant antigen tumor vaccines. These vaccines elicited biological responses in about 50% of the patients and clinical responses in limited number of patients. However, major problems remain for the development of clinically effective tumor vaccines. These problems are caused primarily by the mechanisms that tumor cells are using to avoid detection and destruction by the immune system. Our objective has been to identify, characterize and reverse these escape mechanisms. METHODS: Immunohistochemical staining of tissue sections using appropriate mabs; immunoprecipitation; RT-PCR of cytokine transcripts and CD3 transcripts; mitogen-induced proliferation assays of human PBMC; Elisa determinations of IL12p70 and IL-12p40 homodimer. RESULTS: In an extensive series of studies we have identified: (a) downregulation or absence of expression of HLA class I on the cell surface of epithelial ovarian carcinoma (EOC) and breast adenocarcinoma tumor cells; (b) downregulation or absence of expression of CD3zeta transcripts and protein in TIL from EOC and breast adenocarcinoma; (c) production by tumor cells and/or normal cells of immunosuppressive cytokines, such as IL-10 and TGF-beta EOC and breast adenocarcinoma; (d) production by breast adenocarcinoma tumor cell lines of IL-12p40 homodimers. CONCLUSIONS: Although substantial progress has been made, additional studies are needed to overcome these escape mechanisms of human tumors in order to develop effective tumor vaccines.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 903 (Cancer immunity).