title: TCR mimic monoclonal antibodies induce apoptosis of tumor cells via immune effector-independent mechanisms.
abstract: mAbs that recognize peptides presented on the cell surface by MHC class I molecules are potential therapeutic agents for cancer therapy. We have previously demonstrated that these Abs, which we termed TCR mimic mAbs (TCRm), reduce tumor growth in models of breast carcinoma. However, mechanisms of TCRm-mediated tumor growth reduction remain largely unknown. In this study, we report that these Abs, in contrast to several mAbs used currently in the clinic, destroy tumor cells independently of immune effector mechanisms such as Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). We found that TCRm-mediated apoptosis of tumor cells was associated with selective and specific binding of these Abs to peptide/HLA class I complexes, which triggered the activation of JNK and intrinsic caspase pathways. This signaling was accompanied by the release of mitochondrial cytochrome c and apoptosis-inducing factor. TCRm-induced apoptosis in tumor cells was completely inhibited by soluble MHC tetramers loaded with relevant peptide as well as with inhibitors for JNK and caspases. Furthermore, mAbs targeting MHC class I, independent of the peptide bound by HLA, did not stimulate apoptosis, suggesting that the Ab-binding site on the MHC/peptide complex determines cytotoxicity. This study suggests the existence of mechanisms, in addition to ADCC and CDC, through which these therapeutic Abs destroy tumor cells. These mechanisms would appear to be of particular importance in severely immunocompromised patients with advanced neoplastic disease, since immune cell-mediated killing of tumor cells through ADCC and CDC is substantially limited in these individuals.
authors.affiliation: Department of Biomedical Sciences, Center for Immunotherapeutic Research, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Verma
authors.forename: Rinki
authors.initials: R
authors.lastname: Jain
authors.forename: Shannon
authors.initials: S
authors.lastname: Caseltine
authors.forename: Aaron
authors.initials: A
authors.lastname: Rennels
authors.forename: Raktima
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Markiewski
authors.forename: Amit
authors.initials: A
authors.lastname: Rawat
authors.forename: Francisca
authors.initials: F
authors.lastname: Neethling
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bickel
authors.forename: Jon A
authors.initials: JA
authors.lastname: Weidanz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell