Immunity and immunosuppression in the tumor-host interaction
Author: Petersson, Max
Date: 1999-12-16
Location: Föreläsningssalen vid Mikrobiologiskt och Tumörbiologiskt Centrum, Karolinska Institutet, Theorells väg 1
Time: 10.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
With the advent of new methods in molecular biology and in peptide
isolation, a number of tumor-associated antigens and their epitopes have
been identified and characterized. However, tumors often grow
progressively evolving different mechanisms of immune escape, resulting
in resistance to MHC class I-restricted tumor-specific T cells. This
thesis addresses the recognition of tumor cells by both NK cells and
tumor-specific, MHC class Irestricted T cells. Moreover, I describe the
mechanisms by which the cytokines interleukin 10 (IL-10) and IFN-gamma
(IFN-[gamma]) can modulate MHC class I expression and the recognition by
tumor specific cytotoxic T cells (CTLs) and NK cells.
In my attempts to study tumor specific T-cell responses I have used two
model systems. In the first one, naturally processed peptides were eluted
from RMA lymphoma cells and then tested for their ability to restore the
sensitivity to CTLs of the processing/presentation defective mutant line
RMA-S. This allowed identification of one peptide fraction carrying a
tumor antigen recognized by autologous anti-RMA CTLs. Isolated fractions
loaded onto RMA-S cells could be used to induce anti-tumor CTLs in vivo.
In the second system, autologous CTLs were generated against
methylcholanthrene (MC)-induced mouse sarcomas. These tumors are known to
carry unique tumor-specific antigens, and CTLs against one specific tumor
will not react against another. Tumor specificity was confirmed in
TNF-[alpha] release assays, concurring with in vivo rejection tests.
Peptides eluted from MC sarcomas were fractionated by rpHPLC. Only one
and unique HPLC fraction from each of the three different tumor-derived
peptide eluates capacitated RMA-S to induce TNF-[alpha] release by the
specific CTLs. Further, these unique antigenic fractions were all H-2K b
restricted. In conclusion, my data indicate that CTL responses against MC
induced sarcomas focus on one MHC class I presented antigenic peptide,
distinct for each tumor.
The first tumor model system allowed me to dissect a novel T-cell immune
escape mechanism which is based on the immunosuppresive effect of the T
helper 2 cytokine IL-10. 1 showed that IL-10 converts RMA lymphoma cells
to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible
MHC class I expression. IL-10 is the first cytokine reported to have
these effects. This finding was also confirmed in human melanoma cells
when treatment with rIL-10 resulted in a dose-dependent inhibition of
CTL-mediated, HLA-A2. I -restricted, tumor-specific lysis and enhanced
cytotoxic activity by NK cells. When IL-10 was expressed in the RMA
lymphoma this was found to inhibit TAP-dependent translocation of
peptides to the endoplasmic reticulum (ER), resulting in accumulation of
immature MHC-I in the ER and subsequently low levels of MHC class I at
the cell surface. Furthermore I have found that constitutive IL-10
production accounts for the high NK sensitivity, low MHC-I expression and
poor TAP1/2 function in the prototype NK target YAC-1. I have also
determined that a T cell independent in vivo mechanisms can revert this
ability of YAC-1 cells to produce IL-10, thus restoring the MHC-I
expression and TAP 1/2 function of these cells. Interferons are cytokines
which can enhance tumor cell expression of MHC class 1, thereby making
tumors less sensitive to NK cells. In an experimental model of metastasis
I used the B 16 mouse melanoma. Pre-treatment of the melanoma cells with
IFN-gamma enhanced their metastatic potential and their MHC class I
expression concomitantly with protecting these tumor cells from NK lysis.
Thus, IL-10 is the first cytokine shown to affect TAP expression/function
and thereby MHC class I expression, which results in increased
sensitivity to natural killer cells and reduced/loss of sensitivity to
cytotoxic T-lymphocytes. In addition, IFN-[gamma] apper to have the
reversed effects on these parameters. Through an increased knowledge of
the antigens expressed on tumors and of the mechanisms tumors use to
evade the immune system, novel aproaches could be developed and
introduced in the treatment of cancer.
List of papers:
I. Franksson L, Petersson M, Kiessling R, Karre K (1993). "Immunization against tumor and minor histocompatibility antigens by eluted cellular peptides loaded on antigen processing defective cells. " Eur J Immunol 23(10): 2606-2613
Pubmed
II. Kono K, Petersson M, Ciupitu AM, Wen T, Klein G, Kiessling R. (1995). "Methylcholanthrene-induced mouse sarcomas express individually distinct major histocompatibility complex class I-associated peptides recognized by specific CD8+ T-cell lines. " Cancer Res 55(23): 5648-5655
Pubmed
III. Taniguchi K, Petersson M, Hoglund P, Kiessling R, Klein G, Karre K (1987). "Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens. " Proc Natl Acad Sci U S A 84(10): 3405-3409
Pubmed
IV. Petersson MG, Karre K, Cochet M, Kourilsky P, Kiessling R (1987). "An active T-cell-independent mechanism enhances MHC class I transcription and expression on a mouse T-cell lymphoma in vivo. " Cell Immunol 108(2): 460-472
Pubmed
V. Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, Zhang QJ, Masucci MG, Kiessling R (1994). "Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. " J Exp Med 180(6): 2371-2376
Pubmed
VI. Salazar-Onfray F, Petersson M, Franksson L, Matsuda M, Blankenstein T, Karre K, Kiessling R (1995). "IL-10 converts mouse lymphoma cells to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible MHC class I expression. " J Immunol 154(12): 6291-6298
Pubmed
VII. Petersson M, Charo J, Salazar-Onfray F, Noffz G, Mohaupt M, Qin Z, Klein G, Blankenstein T, Kiessling R (1998). "Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1." J Immunol 161(5) 2099-2105
Pubmed
VIII. Salazar-Onfray F, Charo J, Petersson M, Freland S, Noffz G, Qin Z, Blankenstein T, Ljunggren HG, Kiessling R (1997). "Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10. " J Immunol 159(7): 3195-3202
Pubmed
IX. (1970). " "
I. Franksson L, Petersson M, Kiessling R, Karre K (1993). "Immunization against tumor and minor histocompatibility antigens by eluted cellular peptides loaded on antigen processing defective cells. " Eur J Immunol 23(10): 2606-2613
Pubmed
II. Kono K, Petersson M, Ciupitu AM, Wen T, Klein G, Kiessling R. (1995). "Methylcholanthrene-induced mouse sarcomas express individually distinct major histocompatibility complex class I-associated peptides recognized by specific CD8+ T-cell lines. " Cancer Res 55(23): 5648-5655
Pubmed
III. Taniguchi K, Petersson M, Hoglund P, Kiessling R, Klein G, Karre K (1987). "Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens. " Proc Natl Acad Sci U S A 84(10): 3405-3409
Pubmed
IV. Petersson MG, Karre K, Cochet M, Kourilsky P, Kiessling R (1987). "An active T-cell-independent mechanism enhances MHC class I transcription and expression on a mouse T-cell lymphoma in vivo. " Cell Immunol 108(2): 460-472
Pubmed
V. Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, Zhang QJ, Masucci MG, Kiessling R (1994). "Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. " J Exp Med 180(6): 2371-2376
Pubmed
VI. Salazar-Onfray F, Petersson M, Franksson L, Matsuda M, Blankenstein T, Karre K, Kiessling R (1995). "IL-10 converts mouse lymphoma cells to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible MHC class I expression. " J Immunol 154(12): 6291-6298
Pubmed
VII. Petersson M, Charo J, Salazar-Onfray F, Noffz G, Mohaupt M, Qin Z, Klein G, Blankenstein T, Kiessling R (1998). "Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1." J Immunol 161(5) 2099-2105
Pubmed
VIII. Salazar-Onfray F, Charo J, Petersson M, Freland S, Noffz G, Qin Z, Blankenstein T, Ljunggren HG, Kiessling R (1997). "Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10. " J Immunol 159(7): 3195-3202
Pubmed
IX. (1970). " "
Issue date: 1999-11-25
Publication year: 1999
ISBN: 91-628-3931-4
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