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

The urgent need to recover MHC class I in cancers for effective immunotherapy

“…We showed that the prototypic TEIPP epitope, derived from the housekeeping protein Trh4, is processed by signal peptide peptidase and is, therefore, processed independently of TAP or the proteasome [69]. In a novel TCR transgenic mouse model based on the Trh4-specific CD8 + T cell clone, we observed an efficient thymic selection of these T cells, indicating that the TEIPP T cell repertoire is not affected by central tolerance [70 •• ]. In addition, the TEIPP T cells were effective in tumor control of the TAP-deficient RMA-S tumor.…”

TAP-ing into TIEPPs for cancer immunotherapy

“…Yet, what sets TEIPPs apart from tumor-derived neoantigens is that they are derived from normal, nonmutated, ubiquitously expressed, germline-encoded housekeeping proteins. can be efficiently primed by cross-presentation through vaccination with the same long TEIPP peptide and that this can result in activation of cytolytic CD8 + TEIPP-specific T cells (11). This observation gives rise to the key question as to whether vaccine-induced, TEIPP-specific T cells can protect against tumor growth in a therapeutic setting.…”

“…These concerns are appropriate, as serious adverse events resulting from targeting overexpressed, nonmutated differentiation antigens have been recently reported (9, 10). Doorduljn et al address these concerns and demonstrated that TEIPPspecific T cells are innocuous when transferred into syngeneic B6 mice -even in the presence of inflammatory signals induced by agonistic anti-CD40 antibody (11). As a control, transfer of T cells into TAP-deficient mice, which express TEIPP epitopes, resulted in clear signs of antigen activation.…”

“…In this issue, Doorduljn et al (11) have studied the potential autoimmunity that may develop with TEIPP-based immunotherapy by constructing a T cell receptor-transgenic (TCR-tg) mouse model bearing a MHC-I-restricted (H-2 D b ) TCR against the prototypic TEIPP antigen TRH4. Using this model, Doorduljn and colleagues have studied thymic selection and function of TEIPP-specific T cells in a way that has hitherto not been possible.…”

CIMT 2016: Mechanisms of efficacy in cancer immunotherapy — Report on the 14th Annual Meeting of the Association for Cancer Immunotherapy May 10–12 2016, Mainz, Germany

“…TEIPPs originate from universal housekeeping proteins, are processed independently of the peptide transporter TAP and are only presented by the residual MHC class I molecules on cancer cells with impaired TAP functions 20,21 . Utilizing the lack of central tolerance, van Hall and colleagues demonstrated strong immunogenicity of these TEIPPs and induced TEIPP-specific T cells upon vaccination of TAP-deficient mice with synthetic long peptides (SLP) 22 . Immunization with TEIPP antigens may be beneficial especially in advanced, immune-edited tumors, where vaccination against neo-antigens may lose its effectiveness due to impaired TAP processing.…”