Abstract:
Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.
摘要:
具有PD-1/PD-L1抑制的免疫检查点阻断(ICB)彻底改变了非小细胞肺癌(NSCLC)的治疗。持久的响应,然而,仅在患者亚群中观察到。有缺陷的抗原呈递和免疫抑制性肿瘤微环境(TME)可导致T细胞募集不足和ICB抗性。我们评估了CXCL9和CXCL10工程化树突状细胞(CXCL9/10-DC)的肿瘤内(IT)疫苗接种作为克服耐药性的策略。ITCXCL9/10-DC导致TME中增强的T细胞浸润和活化以及小鼠NSCLC模型中的肿瘤抑制。ITCXCL9/10-DC的抗肿瘤功效依赖于CD4+和CD8+T细胞,以及CXCR3依赖性T细胞从淋巴结运输。ITCXCL9/10-DC,结合ICB,克服抗性并在鼠模型中建立系统性肿瘤特异性免疫。这些研究提供了对CXCL9/10-DC介导的宿主免疫激活的机制理解,并支持ITCXCL9/10-DC的临床翻译以增强NSCLC中的ICB功效。