Cutting edge: permissive MHC class II allele changes the pattern of antitumor immune response resulting in failure of tumor rejection - PubMed (original) (raw)

Comparative Study

Cutting edge: permissive MHC class II allele changes the pattern of antitumor immune response resulting in failure of tumor rejection

Elena N Klyushnenkova et al. J Immunol. 2009.

Abstract

We studied the growth of transgenic adenocarcinoma of mouse prostate (TRAMP)-C1 tumor cells expressing human prostate-specific Ag (PSA) in HLA-DRB1*1501 (DR2b) transgenic mice. TRAMP-PSA tumors were frequently rejected by HLA-DR2b(-) mice but had increased incidence in HLA-DR2b(+) littermates. The levels of PSA-specific CD8 T cell responses were significantly higher in the HLA-DR2b(-) mice that rejected TRAMP-PSA tumors compared with HLA-DR2b(+) tumor-bearing littermates. In contrast, Ab responses to PSA were strong in HLA-DR2b(+) mice bearing TRAMP-PSA tumors and were virtually undetectable in HLA-DR2b(-) littermates. The analysis of CD4 T cell responses to PSA revealed the presence of several CD4 T cell epitopes in HLA-DR2b(+) mice but failed to identify strong I-A(b)-restricted epitopes in HLA-DR2b(-) mice. Our data demonstrate that the expression of a permissive HLA class II allele can change the pattern of the immune response to a tumor Ag, resulting in the failure of tumor rejection.

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Figures

Figure 1

Figure 1. TRAMP tumor cell growth in HLA-DR2bxB6 F1 mice

(A) TRAMP-C1 (left panel) or TRAMP-PSA (right panel) tumor cells were inoculated s.c. into HLA-DR2b+ or HLA-DR2b- F1 male mice. Tumor growth was monitored as described in Materials and Methods, p values (log rank test) are displayed on the graphs. (B) TRAMP-PSA tumor cells were inoculated s. c. into HLA-DR2b+ (left panel) and HLA-DR2b- (right panel) F1 male mice in Matrigel. The implants were harvested two weeks later, and PSA expression in the tissue sections was detected as described in Materials and Methods. Magnification 200x.

Figure 2

Figure 2. PSA-specific CD8 T cell response to PSA-expressing TRAMP tumor cells in HLA-DR2bxB6 F1 mice

(A) HLA-DR2b+ or HLA-DR2b- F1 mice were inoculated s.c. with TRAMP-PSA tumor cells. Spleens were harvested two weeks later, and frequencies of IFN-γ secreting cells were estimated by ELISPOT assay as described in Materials and Methods. Lymphocytes from 5 mice per group were tested individually in triplicates, mean ± SE was calculated for each group. Combined data from two independent experiments with similar trend are shown. (B) HLA-DR2b+ F1 or wild type B6 mice were inoculated s.c. with TRAMP-PSA tumor cells. Two weeks later, tumor-bearing and syngeneic naïve animals were injected i.v. with CFSE-labeled target cells. A mixture consisted of equal numbers (10×106 each per mouse) of CFSEhigh cells pulsed with PSA65-73 peptide and CFSElow untreated cells. Spleens were removed 16 hr later, and analyzed for the loss of CFSEhigh population by flow cytometry. CFSElow/CFSEhigh ratios are presented as a box plot, the boundaries of the box show the 5th/95th percentile, a line within the box marks the median. Combined data from three independent experiments with similar trend are shown (total 9 mice per group). * p<0.05, ** p<0.01, *** p<0.001 (two-tailed Mann-Whitney U-test).

Figure 3

Figure 3. PSA-specific humoral immune response to the PSA-expressing TRAMP tumor cells in HLA-DR2bxB6 F1 mice

Mice were inoculated with TRAMP-PSA tumor cells as described in Figure 2. Blood was collected two weeks after tumor inoculation. PSA Ab response was measured by ELISA. The titration curves are shown for the individual mice (5 mice per group, same animals as depicted in Figure 2A).

Figure 4

Figure 4. CD4 T cell response to soluble PSA in HLA-DR2bxB6 F1 mice

HLA-DR2b+ or HLA-DR2b- F1 mice were immunized s.c. with human PSA in CFA. Spleens were harvested two weeks later, and lymphocytes were cultured in the presence of soluble PSA or a series of overlapping 20-mer peptides derived from the primary amino acid sequence of human PSA. The response to the purified protein derivate (PPD) of tuberculin served as a positive control. IFN-γ secretion was measured by ELISPOT. Stimulatory index was calculated by equation: [Spot number (sample)] / [Spot number (no Ag)]. Data are means ± SD of triplicates.

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