Antigen-specific tumor vaccine efficacy in vivo against prostate cancer with low class I MHC requires competent class II MHC.
BACKGROUND
Cancers can escape immune recognition by means of evading class I major histocompatibility complex (MHC) -mediated recognition by cytotoxic T lymphocytes. However, immunization strategies targeting defined tumor-associated antigens have not been extensively characterized in murine prostate cancer models. Therefore, we evaluated antigen-specific, antitumor immunity after antigen-encoding vaccinia immunization against mouse prostate cancer cells expressing a model tumor-associated antigen (beta-galactosidase) and exhibiting partially deficient class I MHC.


RESULTS
Low class I MHC expression in beta-galactosidase-expressing D7RM-1 prostate cancer cells was shown by fluorescence activated cell sorting, and deficient class I MHC-mediated antigen presentation was shown in resistance of D7RM-1 to cytolysis by beta-galactosidase-specific cytotoxic T lymphocytes (CTL). Despite partially deficient class I MHC presenting function, immunization with vaccinia encoding beta-galactosidase conferred antigen-specific protection against D7RM-1 cancer. Antigen-specific immunity was recapitulated in beta(2)m knockout mice (with deficient class I MHC and CTL function), confirming that class I MHC antigen presentation was not required for immunity against tumor partially deficient in class I MHC. Conversely, antigen-specific antitumor immunity was abrogated in A(b)beta knockout mice (with deficient class II MHC and helper T cell function), demonstrating a requirement for functional class II MHC. Resistant tumors from the otherwise effectively immunized beta(2)m knockout mice (among which tumor progression had been reduced or delayed) showed reduced target antigen expression, corroborating antigen-specificity (and showing an alternative immune escape mechanism), whereas antigen expression (like tumor growth) was unaffected among A(b)beta knockout mice.


CONCLUSIONS
Our results demonstrate that class I MHC-restricted antigen presentation and CTL activity is neither necessary nor sufficient for antigen-encoding vaccinia immunization to induce protective immunity against class I MHC-low tumors, whereas host class II MHC-mediated antigen presentation facilitates antigen-specific immunity against prostate cancer in vivo. Reduced expression of the target antigen developed rapidly in vivo as an immune escape mechanism for such cancers.
Neeley
Yilin C
YC
Department of Urology, University of Michigan, Ann Arbor, Michigan 48109-0330, USA.
McDonagh
Kevin T
KT
Overwijk
Willem W
WW
Restifo
Nicholas P
NP
Sanda
Martin G
MG
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000235:genetics; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; D001616:beta-Galactosidase