Immune Recognition Of Tumor Stress Proteins

What explanations exist for the correlation of immunogenicity and stress protein expression of tumors?

(1) Stress proteins can be recognized by NK cells if they are aberrantly expressed on the cell surface of tumor cells [17, 29], Multhoff and coworkers [29] described either an heat inducible surface expression of HSP 72 on human sarcoma cells, or a stable HSP 72 surface expression on human colon carcinoma cells [17]. The extent of HSP 72 expression correlated with NK-cell lysis. The NK-cell lysis of tumor cells expressing surface HSP 72 could be blocked by antibodies against HSP 72, indicating that HSP 72 on the surface of tumor cells serves as a NK-cell recognition structure.

(2) Stress protein peptide antigens can be recognized by HLA class-II restricted tumor infiltrating lymphocytes (TIL) and may augment a specific immune response against tumors. CD4 positive TIL recognized antigen presenting cells (APC) pulsed with HSP 70 and stressed APC in an HLA-DR restricted fashion [30], An increased HSP 70 expression by tumor stroma cells, or by tumor cells themselves, may lead to this T-cell response.

(3) Stress proteins on the surface of tumor cells can present peptide antigens to certain T-cell populations. Tamura and coworkers [31] reported that an H-ras transformed rat fibrosarcoma-cell line expresses HSP 70 molecules on the cell surface which can be recognized by syngenic CD3 positive, CD4, CD8 and a/3-TCR negative T cells, presumably yS-T cells. The T-cell recognition was shown to be peptide dependent but MHC-unrestricted [32], suggesting that surface HSP 70 on tumor cells can act as an antigen presenting molecule for yS-T cells. HSP 70 expressing tumor cells in this system were more immunogenic in vivo than HSP 70 negative cells, supporting the in vivo relevance of HSP 70 surface expression [31]. A corresponding example was found for a human B-cell lymphoma line, which was shown to be recognized by autologous /<5-T cells. These yS-T-cell lines recognized an immunoglobulin peptide presented by an HSP 70 surface molecule [33]. (4) Tumor-derived HSP 70, 90 and gp96 stress proteins were identified as tumor-specific transplantation antigens of chemically induced mouse tumors [34-37]. It was demonstrated in different tumor models that preparations of stress proteins HSP 70, 90 and gp96 from mouse tumors elicit a protective and specific T-cell mediated immunity against the tumor from which the stress protein was derived [38],

The observations under items (3) and (4) have strong implications for vaccine development against cancer, because they suggest that active immunization with stress protein preparations from tumors can elicit tumor-specific T-cell responses and immunologically mediated tumor regressions. This will be reviewed and discussed in the subsequent part of the article.

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