Tumor-specific immunity can be enhanced by transfection of tumor cells with syngeneic MHC-class-II genes or allogeneic MHC-class-I genes

Abstract

Enhancing a host's immune response to autologous tumor has been a goal of tumor immunology for many years. Approximately 15 years ago, the most promising potential immunotherapies for tumors involved the in vivo nonspecific activation of lymphocytes with agents such as bacilla Calmette-GuCrin (BCG), Corynebacterium parvum, or levamisole. The hope of these treatments was that an overall in vivo stimulation of the immune response would result in increased tumor-specific activity. These approaches, however, were unsuccessful (Terry and Rosenberg, 1982), and led to the conclusion that effective immunotherapy would require treatments that could be specifically targeted to tumor cells. Subsequent to these studies, approaches using tumor-specific strategies have been developed. These include targeting specific effector molecules (e.g., toxins, radioisotopes, etc.) to tumor cells via tumorspecific monoclonal (MAb) and polyclonal antibodies (Vitetta and Uhr, 1985;Wright and Cox, 1987), heteroconjugated antibodies (Segal and Wunderlich, 1988), immunization with tumor cells that have been chemically or physically modified and/or in the presence of adjuvants (Morton, 1986), and adoptive transfer of lymphokineactivated killer (LAK) cells (Rosenberg and Lotze, 1986). These approaches are in various stages of development and/or clinical trial.The development of recombinant DNA technology has provided additional avenues for tumor-specific treatment strategies. Using these techniques, we have recently developed 2 approaches for improving tumor-specific immunotherapy. The first approach is based on the premise that the autologous immune response will be increased if tumor-specific T, cell generation is improved. We have rationalized that if tumor cells are transfected with, and express, MHC-class-11 molecules, they can function directly as antigen-presenting cells (APC) and thereby avoid the need for third-party professional APC. Recent results support this hypothesis and demonstrate that class-11-expressing mouse sarcoma cells are rejected by the autologous host, while class-11-negative wild-type tumor is lethal (Ostrand-Rosenberg et at., 1990b). In the present studies we show that the protective effect of MHCclass-11-antigen expression requires the cytoplasmic domain of the class-I1 molecule, and hence is probably dependent on intra-cellular signalling events.An alternative approach to improving tumor-specific immunity has involved the introduction by gene transfection of allogeneic MHC-class-I genes into mouse tumors. Previous studies indicated unexpectedly that expression of an allogeneic H-2K gene did not produce immunity (Cole et al., 1987). In the present studies, however, we demonstrate that expression of an allogeneic H-2D gene does confer immunity, and that the transfectants successfully immunize against a challenge of wild-type tumor. 'To whom correspondence and reprint requests should be addressed.

Capsid-Specific Cytotoxic T Lymphocytes Recognize Three Distinct H-2Db-Restricted Regions of the BeAn Strain of Theiler's Virus and Exhibit Different Cytokine Profiles

“…b or H-2D b (6,35). To our surprise, VP2 165-173 -specific killing appears to be restricted by D b rather than K b , since L929-D b transfectants but not L929-K b transfectants were killed in a peptide-specific manner (Fig.…”

Major histocompatibility complex class II-transfected tumor cells present endogenous antigen and are potent inducers of tumor-specific immunity

“…In previous studies, immunotherapeutic potential of SaI transfectants correlated with their tumorigenicity (2,8,15,30 ϩ T cells. Since our hypothesis is that class II-transfected tumor cells would be more efficient presenters of any class II-restricted endogenous antigen, SaI sarcoma cells were transfected with the HEL gene, and presentation of lysozyme as an endogenous antigen has been assessed.…”

Therapy of murine mammary carcinoma metastasis with interferon γ and MHC gene-transduced tumour cells

“…Protection from tumour growth in preimmunised animals has been obtained with tumour cells transduced with genes for various cytokines and surface antigens (Tanaka et al, 1986;Ostrand-Rosenberg et al, 1991;Colombo and Forni, 1994). However, realistic therapeutic protocols, in which engineered cells are administered only after the challenge with live parent tumour cells, have been explored less frequently.…”