Sultan Hussein, Trillo-Tinoco Jimena, Rodriguez Paulo, Celis Esteban
Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
Biochemistry and Cancer Biology Department, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
Oncotarget. 2017 Jul 29;8(41):70317-70331. doi: 10.18632/oncotarget.19688. eCollection 2017 Sep 19.
Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated ∼ 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice. Boosting with BiVax in combination with αCD40 antibody (TriVax) or BiVax in combination with IL-2/αIL-2 antibody complexes (IL2Cx) significantly increased the immune responses (∼30-50%). Interestingly, although both boosts were equally effective in generating vast T cell responses, BiVax/IL2Cx showed better control of tumor growth than TriVax. However, this effect was associated with high incidence of diabetes in an antigen and CD8 dependent fashion. T cell responses generated by BiVax/IL2Cx, but not those generated by TriVax were highly resistant to PD-1/PD-L1 inhibitory signals. Nevertheless, PD-1 blockade enhanced the ability of TriVax to control tumor growth but increased the incidence of diabetes. Finally, we show that severe autoimmunity by BiVax/IL2Cx was prevented while preserving outstanding antitumor responses by utilizing a tumor antigen not expressed in the pancreas. Our data provides a clear evidence that peptide based vaccines can expand vast endogenous T cell responses which effectively control tumor growth but with high potential of autoimmune pathology.
免疫疗法在治疗癌症方面已取得了巨大成功。不幸的是，这种成功常常伴随着严重的自身免疫病理反应。在本研究中，我们使用转基因RIP-gp小鼠模型来评估肽疫苗接种的抗肿瘤治疗益处，同时评估可能相关的自身免疫病理反应。我们报告称，棕榈酰化的gp33-41肽和聚肌胞苷酸佐剂疫苗（BiVax）在野生型和假定免疫耐受的RIP-gp小鼠中产生了约5-10%的抗原特异性T细胞反应。用BiVax联合αCD40抗体（TriVax）或BiVax联合IL-2/αIL-2抗体复合物（IL2Cx）进行加强免疫显著增强了免疫反应（约30-50%）。有趣的是，尽管两种加强免疫在产生大量T细胞反应方面同样有效，但BiVax/IL2Cx在控制肿瘤生长方面比TriVax表现更好。然而，这种效果与以抗原和CD8依赖方式出现的高糖尿病发病率相关。由BiVax/IL2Cx产生的T细胞反应，而不是由TriVax产生的T细胞反应，对PD-1/PD-L1抑制信号具有高度抗性。尽管如此，PD-1阻断增强了TriVax控制肿瘤生长的能力，但增加了糖尿病的发病率。最后，我们表明，通过使用胰腺中不表达的肿瘤抗原，在保留出色的抗肿瘤反应的同时，预防了BiVax/IL2Cx引起的严重自身免疫。我们的数据提供了明确的证据，即基于肽的疫苗可以扩大大量内源性T细胞反应，有效控制肿瘤生长，但具有引发自身免疫病理反应的高可能性。
