Killing tumor cells through their surface β₂‐microglobulin or major histocompatibility complex class I molecules

Abstract

Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for b 2 -microglobulin (b 2 M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against b 2 M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-c2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although b 2 M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting b 2 M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for b 2 M/MHC class I-expressing malignancies.

TCR Mimic Monoclonal Antibodies Induce Apoptosis of Tumor Cells via Immune Effector-Independent Mechanisms

“…mAbs that cross-link MHC class I complexes independently of peptide specificity have been shown to activate several intracellular signaling pathways, including 1) phosphorylation of tyrosine kinases, 2) activation of the JAK/STAT pathway, and 3) upregulation of PI3K, leading to JNK activation (17,18,21,(38)(39)(40)(41). Furthermore, these cross-linking mAbs also have been reported to induce apoptosis through caspase-dependent and caspaseindependent mechanisms in B and T lymphocytes and in B cell malignancies.…”

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

“…Cell surface HLA class I and b2-microglobulin complex have been expected as a target for antibody therapy in MM cells. 26 Previously, we have demonstrated that HLA class I molecules are overexpressed in MM cells and that a recombinant single-chain Fv diabody against this molecule efficiently crosslinks HLA class I and induces rho-mediated actin aggregation, which leads to MM cell death without effector function. 27,28 In this study, we generated a new diabody specific to HLA class I molecule (C3B3) and investigated its potential on cancer stem cell-like fraction of MM cell lines and primary MM cells, focusing on the regulation of b-catenin and pluripotency-associated transcription factors.…”

The Adaptor Protein Bam32 in Human Dendritic Cells Participates in the Regulation of MHC Class I-Induced CD8+ T Cell Activation

“…MHC class I molecules are important signal-transducing molecules involved in the finely tuned regulation of immune responses. The downstream events of Ab-mediated engagement of MHC class I molecules have mainly been studied in the context of apoptosis induction and are still poorly understood (29). Based on our results, we hypothesized an involvement of the adapter molecule Bam32 in the downstream events of MHC class I engagement in mature DC.…”