Photoactivated 8-methoxypsoralen treatment causes a peptide-dependent increase in antigen display by transformed lymphocytes.
Ex vivo exposure of malignant human T cells to photoactivated 8-methoxypsoralen (8-MOPa), followed by their i.v. return, appears to vaccinate patients against tumor-associated antigens of cutaneous T cell lymphoma in a procedure termed photopheresis. The molecular basis of this Food and Drug Administration-approved therapy, administered in 100 centers worldwide, is unclear. Most of the attention to the mechanism of action of the drug has focused on its capacity to form covalent cross-links with pyrimidine bases of DNA, thereby inhibiting cellular proliferation. Because immunologic factors appear to be important in the clinical response and could potentially serve as a model for immunotherapy of other malignancies, we explored the possibility that 8-MOP-treated cells display increased quantities of antigenic peptides at their cell surface. In this work, human B-lymphoblastoid tissue culture lines were exposed to 8-MOPa and expression of cell surface class I major histocompatibility complex proteins assessed, since CD8 T cells recognize antigenic moieties in the context of class I molecules. A peak 200-300% increase in MHC class I expression in 8-MOPa-treated cells occurred at 20 hr. 8-MOPa was far more effective in inducing this increase in class I MHC than other modalities, including mitomycin C, gamma-irradiation, ultraviolet B or heat or cold shock. This increase in surface class I MHC molecules appears to be driven by the degradation of cytoplasmic proteins into small peptides, followed by the transport of these peptides to MHC class I molecules in the endoplasmic reticulum. The data suggest that 8-MOPa treatment may augment the immunogenicity of tumor and/or antigen-presenting cells by enhancing processing and transport of class I MHC antigenic peptides.
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520-8059, USA. douglas.hanlon@yale.edu
D J
DJ
Hanlon
C L
CL
Berger
R L
RL
Edelson
D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018122:B7-1 Antigen / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D015395:Histocompatibility Antigens Class I / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008730:Methoxsalen / Q000494:pharmacology*; D011701:PUVA Therapy; D017319:Photosensitizing Agents / Q000494:pharmacology*
D018122:B7-1 Antigen; D015395:Histocompatibility Antigens Class I; D017319:Photosensitizing Agents; D008730:Methoxsalen