Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.

https://cancerres.aacrjournals.org/content/canres/61/12/4766.full.pdf

Regulatory CD4+CD25+ T Cells in Tumors from Patients with Early-Stage Non-Small Cell Lung Cancer and Late-Stage Ovarian Cancer

CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin.

http://www.linkgroup.hu/docs/pcs/98pharmther.pdf

The 90-kDa molecular chaperone family : structure, function, and clinical applications. A comprehensive review

The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90- kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major molecular chaperones of the cytosol and of the endoplasmic reticulum, respectively) has become an increasingly active subject of research in the past couple of years. These ubiquitous, well-conserved proteins account for 1-2% of all cellular proteins in most cells. However, their precise function is still far from being elucidated. Their involvement in the aetiology of several autoimmune diseases, in various infections, in recognition of malignant cells, and in antigen-presentation already demonstrates the essential role they likely will play in clinical practice of the next decade. The present review summarizes our current knowledge about the cellular functions, expression, and clinical implications of the 90-kDa molecular chaperone family and some approaches for future research. pharmacol. ther. 79(2):129-168, 1998. © 1998 Elsevier Science Inc.

/pdf/associate-editor-d-shugar-the-90-kda-molecular-chaperone-42hs4t0kau.pdf

Associate Editor: D. Shugar The 90-kDa Molecular Chaperone Family: Structure, Function, and Clinical Applications. A Comprehensive Review

This review examines the role of cross-presentation in tolerance and immunity. We discuss (a) the antigenic requirements for cross-presentation, (b) the phenotype of the antigen presenting cell (APC), (c) the cellular interactions and molecular signals involved in cross-priming, and (d) the factors that direct the immune system toward tolerance or immunity. A large part of this review is dedicated to summarizing our current knowledge of the cross-presenting APC.

Cross-presentation, dendritic cells, tolerance and immunity.

Purified preparations of 96-kDa heat shock proteins (gp96) have been previously shown to elicit tumor-specific immunity to the tumor from which gp96 is obtained but not to antigenically distinct chemically induced tumors. The cellular requirements of gp96-elicited immunity have been examined. It is observed that depletion of CD8+, but not CD4+, T cells in the priming phase abrogates the immunity elicited by gp96. The CD8+ T cells elicited by immunization with gp96 are active at least up to 5 weeks after immunization. Depletion of macrophages by treatment of mice with carrageenan during the priming phase also results in loss of gp96-elicited immunity. In the effector phase, all three compartments, CD4+ and CD8+ T cells and macrophages, are required. Immunity elicited by whole irradiated tumor cells shows a different profile of cellular requirements. In contrast to immunization with gp96, depletion of CD4+, but not CD8+, T cells during priming with whole tumor cells abrogates tumor immunity. Further, ablation of macrophage function during priming or effector phases has no effect on tumor immunity elicited by whole cells. Our results suggest the existence of a macrophage-dependent and a macrophage-independent pathway of tumor immunity. Our observations also show that in spite of exogenous administration, vaccination with gp96 preparations elicits a CD8+ T-cell response in vivo, and it is therefore a useful method of vaccination against cancer and infectious diseases.

https://www.pnas.org/content/pnas/91/8/3077.full.pdf

Cellular requirements for tumor-specific immunity elicited by heat shock proteins: Tumor rejection antigen gp96 primes CD8+ T cells in vivo

Strong CD4 + and CD8 + T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4 + and CD8 + T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8 + T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.

/pdf/heat-shock-protein-mediated-cross-presentation-of-exogenous-10auoauqc1.pdf

Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II.

There are currently over 150 medical centers worldwide enrolling patients in randomized, controlled Phase III clinical trials testing autologous cancer-derived heat-shock protein (HSP)–peptide complexes for the treatment of renal cell carcinoma and melanoma. In addition, autologous HSP–peptide complexes have been or are being tested in Phase I and II trials of chronic myelogenous leukemia, lymphoma and pancreatic, gastric and colorectal cancers. The door has more recently opened to clinical testing of off-the-shelf HSP-based treatments for infectious diseases. This review recounts the long history of basic research on HSPs in immune response. A keen understanding of how these ancient molecules orchestrate the immune response to cancer and infections has been gained, providing a clear rationale for translating this knowledge into clinical medicine.

Daniel L. Levey

Papers

Cellular requirements for tumor-specific immunity elicited by heat shock proteins: Tumor rejection antigen gp96 primes CD8+ T cells in vivo

Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II.

Vaccination with heat shock protein-peptide complexes: from basic science to clinical applications.

Safety and immunogenicity of long HSV-2 peptides complexed with rhHsc70 in HSV-2 seropositive persons

Alterations in T cells of cancer-bearers: whence specificity?