A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens

Abstract

Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers.

New Role of Signal Peptide Peptidase To Liberate C-Terminal Peptides for MHC Class I Presentation

“…This reasoning is in line with our recent findings on a novel category of T cell epitopes presented by cancer cells with TAP defects. We showed that deficiency in the expression of the peptide transporter TAP, a feature frequently found in human cancers, leads to the presentation of a broad repertoire of immunogenic peptides by MHC-I (13)(14)(15)(16)(17). Biochemical characterization of peptide repertoires from TAP-deficient cells and their direct proficient counterparts indeed revealed unique complementing pools of peptides (14,18,19).…”

TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors

“…We previously identified CD8 + T cells that specifically recognize TAP-deficient tumor cells, which were otherwise resistant to antitumor T cells targeting conventional tumor antigens (13)(14)(15)(16). The recognition of these MHC-I lo tumors depends on TCR/ MHC-I interactions and targets a novel class of antigens, called TEIPP (T cell epitopes associated with impaired peptide processing).…”

Z-100, an Immunomodulatory Extract of <i>Mycobacterium tuberculosis</i> Strain Aoyama B, Prevents Spontaneous Lymphatic Metastasis of B16-BL6 Melanoma

“…23) Tumor MHC class I downregulation has been associated with tumor progression and metastasis. 24) Our present study, along with previous studies of Z-100 showing inhibition of hematogenous metastasis and primary tumor growth in B16 melanoma mice models, [15][16][17] suggest that Z-100 may inhibit cancer progression via a nonspecific increase in immune cells including CD4+ T, CD8+ T, NK and NKT cells. Z-100 may enhance immune responses in the lymph nodes than in other tissues in mice as the doses required to inhibit hematogenous metastasis and primary tumor growth (2, 10 mg/kg, respectively) are higher than that required to inhibit lymph node metastasis (0.1 mg/kg).…”