Elisabeth Z. Wolpert

Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants

Defects in major histocompatibility complex (MHC) class I–restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.

T cell competition for the antigen-presenting cell as a model for immunodominance in the cytotoxic T lymphocyte response against minor histocompatibility antigens

We recently demonstrated that spleen cells primed against dominant BALB.B antigens can inhibit the cytotoxic T lymphocyte (CTL) response against subdominant antigens in vitro. In this study, we show that this interference is dependent on CD8+, but not CD4+, T cells directed against dominant antigens. Similar to immunodominance in vivo, T cell interference in vitro required presentation of dominant and sobdominant antigens by the same antigen‐presenting cell. In vivo priming with cells expressing dominant and subdominant antigens did not induce long‐lasting unresponsiveness against the latter. These results support a model in which immunodominance is mediated by T cell competition. In line with this, we found that the immunodominance effects in the CTL response against these minor histocompatibility antigens could be broken by immunization with live bone marrow‐derived dendritic cells.

Induction of Protective CTL Immunity against Peptide Transporter TAP-Deficient Tumors through Dendritic Cell Vaccination

A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.

IMMUNIZATION WITH DENDRITIC CELLS BREAKS IMMUNODOMINANCE IN CTL RESPONSES AGAINST MINOR HISTOCOMPATIBILITY AND SYNTHETIC PEPTIDE ANTIGENS

We have examined the mechanisms involved in immunodominance in two different experimental models: the cytotoxic T lymphocyte (CTL) response in B6 mice against minor histocompatibility antigens of BALB.B mice, and the response of B6 mice against a mixture of five synthetic peptides corresponding to well‐defined immunogenic epitopes. The CTL responses in these models focus on a few dominant epitopes, whereas no or only weak responses can be detected against other subdominant epitopes. Neither of these immunodominance phenomena can be explained by insufficient presentation of subdominant epitopes in the presence of the dominant ones. Immunodominance could also be demonstrated in an in vitro system, in which B6 splenocytes primed with BALB.B could interfere with the CTL response against subdominant antigens. This interference was dependent on CD8+ T cells and on the simultaneous presentation of dominant and subdominant antigens on the same antigen‐presenting cell, suggesting T cell competition around the antigen‐presenting cell as a potential explanation. The immunodominance in both systems could be broken by immunization with dendritic cells (from BALB.B or from B6 loaded with peptides). This procedure allowed detection of CTL responses against both dominant and previously subdominant antigens. J. Leukoc. Biol. 66: 268–271; 1999.