In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8⁺ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8⁺/CD4⁺ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.

中文翻译：

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解锁 PD-1 抗体耐药性：MUC1 DNA 疫苗增强 CD8+ T 细胞浸润并减弱肿瘤抑制

鉴于某些患者群体对 PD1 抗体治疗的耐药性不断增加，迫切需要进行深入研究。我们的研究采用小鼠 CT26/MUC1 结肠癌模型，评估了 MUC1 DNA 疫苗和 PD1 抗体在克服 PD1 耐药性方面的协同效应。当作为独立治疗时，PD1 抗体对肿瘤生长没有影响。此外，肿瘤内 T 细胞比例或 T 细胞功能没有观察到变化。相比之下，单独施用 MUC1 DNA 疫苗可通过提高 IFN-γ 和颗粒酶 B 的产生来显着增强 CD8 ⁺ T 细胞的细胞毒性。我们令人信服的证据强调，与单一疗法相比，联合疗法更有效地抑制肿瘤生长并延长生存期，从而减轻了单药疗法固有的局限性。这种功效的增强是由肿瘤微环境的显着改变驱动的，使其偏向促免疫条件。这一主张得到了 CD8 ⁺ /CD4 ⁺ T 细胞比率升高和免疫抑制性 MDSC 和 Treg 细胞群减少的支持。在机制方面，协同疗法放大了肿瘤中 CXCL13 的表达水平，随后促进 T 细胞进入肿瘤环境。总之，我们的研究结果主张将综合疗法作为克服 PD1 抗体耐药性的有效机制，利用改善的 T 细胞功能和浸润。这项研究为通过应用创新治疗策略增强抗肿瘤免疫力提供了重要的观点。