Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo.
Summary of "Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo."
Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNγ and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.
Affiliation
Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Kent St., Bentley, Perth, WA, 6102, Australia.
Journal Details
This article was published in the following journal.
Name: Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22714286
- DOI: http://dx.doi.org/10.1007/s00262-012-1307-4
Medical and Biotech [MESH] Definitions
Endodermal Sinus Tumor
An unusual and aggressive tumor of germ-cell origin that reproduces the extraembryonic structures of the early embryo. It is the most common malignant germ cell tumor found in children. It is characterized by a labyrinthine glandular pattern of flat epithelial cells and rounded papillary processes with a central capillary (Schiller-Duval body). The tumor is rarely bilateral. Before the use of combination chemotherapy, the tumor was almost invariably fatal. (From DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1189)
T-lymphocytes, Cytotoxic
Immunized T-lymphocytes which can directly destroy appropriate target cells. These cytotoxic lymphocytes may be generated in vitro in mixed lymphocyte cultures (MLC), in vivo during a graft-versus-host (GVH) reaction, or after immunization with an allograft, tumor cell or virally transformed or chemically modified target cell. The lytic phenomenon is sometimes referred to as cell-mediated lympholysis (CML). These CD8-positive cells are distinct from NATURAL KILLER CELLS and NATURAL KILLER T-CELLS. There are two effector phenotypes: TC1 and TC2.
Antigens, Cd8
Differentiation antigens found on thymocytes and on cytotoxic and suppressor T-lymphocytes. CD8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in MHC (Major Histocompatibility Complex) Class I-restricted interactions.
Cancer Vaccines
Vaccines or candidate vaccines designed to prevent or treat cancer. Vaccines are produced using the patient's own whole tumor cells as the source of antigens, or using tumor-specific antigens, often recombinantly produced.
Neoplasm Proteins
Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (TUMOR MARKERS, BIOLOGICAL) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.
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