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| Abstract |
The use of cancer immunotherapy as part of multidisciplinary therapies for cancer is a promising strategy for the cure of advanced cancer patients. In cancer immunotherapy, the effective priming of tu...mor-associated antigen (TAA)-specific CD8^+ T cells is essential, and therefore, the appropriate selection of the best peptide for targeting the cancer is a most important concern. One criticism in the selection of a TAA is the immunogenicity of the TAA, the vaccination of which effectively elicits clinical responses. However, the critical basic immunological factors that affect the differences in the immunogenicity of TAAs remain to be elucidated. Here we found that CD4 T-cell responses suppressed the immunogenicity of the concomitant TAA in a murine melanoma model in which intratumoral activated dendritic therapy (ITADT) was used for treatment of the established cancer, and we observed that the antitumor effects were largely dependent on the CD8 T-cell response. CD4 T-cell depletion simply enhanced the tyrosinase-related protein (TRP) -2_<180-188> peptide-specific cytotoxic T-cell (CTL) responses, and CD4 T-cell depletion provided immunogenicity for mgp100_<25-33> peptide, to which a CTL response could not be detected at all in CD4 T-cell-intact mice in the early therapeutic phase. Further, the mgp100_<25-33> peptide-specific CTL response again became undetectable after the recovery of CD4 T cells in previously CD4-depleted, tumor-eradicated mice, whereas the TRP-2_<180-188> peptide-specific CTL response was still much stronger in CD4-depleted mice than in CD4-intact mice. These findings suggest that the CD4 T cell-mediated masking effects of the immunogenicity of tumor-associated antigens are qualitatively and quantitatively different depending on the individual antigens.
がん免疫療法の集学的治療は進行がん患者の治癒が期待できる効果的治療である.がん免疫療法では腫瘍関連抗原特異的CD8T細胞応答が必要であり,よって,標的とする癌に最も効果的な腫瘍関連抗原を選択することが重要である.その上で,臨床的抗腫瘍効果を発揮する腫瘍関連抗原の選択において,考慮すべき重要な因子は,その免疫原性である.しかし,現在のところ,腫瘍関連抗原の免疫原性の違いを特徴づけるための基礎免疫学的知見の解明は不十分である.我々はここで,生着腫瘍に活性化樹状細胞を腫瘍内に投与する免疫療法を施行するマウスメラノーマモデル(これはCD8T細胞依存性に抗腫瘍効果を発揮する)において,CD4T細胞が腫瘍抗原の免疫原性を抑制することを見出した.その治療相において,CD4T細胞の除去により,Tyrosinase-relatedprotein(TRP)-2180-188に対するCD8T細胞応答は単純に増強されるのみであったが,CD4が正常なマウスでは検出されないmgp10025-33ペプチドに対するCD8T細胞応答に関してはその検出が可能となった.更にメモリー相において,mgp10025-33ペプチドに対するCD8T細胞応答はCD4T細胞除去後,CD4T細胞が回復すると再びmgp10025-33ペプチドに対するCD8T細胞応答が検出されなくなった.一方で,TRP-2180-188ペプチド応答はCD4T細胞を除去し,治療によって腫瘍を拒絶したマウスの体内にCD4T細胞が回復してきても,CD4T細胞が終始正常なマウスで検出される応答より増強したままの状態であった.これらのことは,CD4T細胞による免疫原性のマスキング効果は個々の腫瘍関連抗原に依存して,質的量的違いを認めることが示唆された.show more
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