The PD-1/B7-H1 Pathway and Melanoma Immunity

肿瘤微环境中的多种因素下调肿瘤免疫，促进肿瘤进展。在黑色素瘤中，主要机制之一是诱导肿瘤特异性T细胞上的共抑制受体，并由肿瘤或肿瘤间质内的其他细胞表达相应的共抑制配体，导致T细胞效应器功能的完全或部分丧失。癌症微环境中放大的共抑制相互作用不仅阻碍免疫肿瘤监测，而且阻碍治疗性免疫干预，这可能解释旨在刺激T细胞的方法失败的原因，包括基于肿瘤抗原的疫苗接种和T细胞刺激性细胞因子。共同抑制相互作用的一个很好的例子是B7-H1(PD-L1)/PD-1途径。我们和其他实验室的早期研究表明，这一途径在逃避癌症免疫方面发挥了关键作用，阻断这一途径可以增强对肿瘤的持续免疫反应。最近使用PD-1全人抗体进行的I期临床试验显示，33%的转移性黑色素瘤患者(n=46)出现了持久的客观(部分和完全)反应。总之，这些研究支持B7-H1作为一种重要的共抑制分子，下调黑色素瘤微环境中的免疫反应，并阻断B7-H1/PD-1途径，成为治疗黑色素瘤的最有前途的方法之一。项目2将向三个方向扩展这些实验室和临床研究结果；具体目标是：目标1：评估人类黑色素瘤微环境中B7-H1/PD-1的表达与抗PD-1治疗的临床反应之间的关系；目标2：研究B7-H1/PD-1阻断在增强抗黑色素瘤免疫和黑色素瘤消退方面的作用机制；以及目标3：通过基于机制的组合方法最大限度地提高黑色素瘤的治疗性免疫。基于我们的发现，黑色素瘤的B7-H1表达直接和广泛地被干扰素上调，B7-H1/PD-1阻断的组合将与IL-2和干扰素-a 2b以及促进肿瘤T细胞渗透的选择性突变BRAF抑制剂一起测试。我们的研究应该对B7-H1/PD-1阻断作为一种新的和有前途的黑色素瘤治疗方法的发展具有直接影响。

Multiple factors in the cancer microenvironment down-regulate tumor immunity and promote tumor progression. In melanoma, one of the dominant mechanisms is the induction of co-inhibitory receptors on tumor-specific T cells and expression of corresponding co-inhibitory ligands by tumor or other cells within tumor stroma, leading to complete or partial loss of T-cell effector functions. Amplified co-inhibitory interactions in the cancer microenvironment impede not only immune tumor surveillance, but also therapeutic immune interventions that may explain the failure of approaches aimed at stimulation of T cells, including tumor antigen-based vaccination and T cell stimulatory cytokines. A prime example of the co-inhibitory interactions is the B7-H1 (PD-L1)/PD-1 pathway. Early studies from our and other laboratories demonstrate a critical role of this pathway in the evasion of cancer immunity, and blockade of this pathway enhances ongoing immune responses against tumors. Recent phase I clinical trials conducted using a fully human antibody to PD-1 demonstrated durable objective (partial and complete) responses in 33% of pretreated metastatic melanoma patients (n=46). Collectively, these studies support B7-H1 as an important co-inhibitory molecule in the down-regulation of immune responses in the melanoma microenvironment and blockade of the B7-H1/PD-1 pathway as one of the most promising approaches for the treatment of melanoma. Project 2 will extend these laboratory and clinical findings in three directions; The specific aims are: Aim 1: to assess the association between B7-H1/PD-1 expression in human melanoma microenvironment with clinical response to anti-PD-1 therapy; Aim 2: to study effector mechanisms of the B7-H1/PD-1 blockade in augmenting anti-melanoma immunity and in melanoma regression; and Aim 3: to maximize melanoma therapeutic immunity by mechanism-based combinatory approaches. Based on our finding that B7-H1 expression by melanoma is directly and extensively up-regulated by interferons, the combination of B7-H1/PD-1 blockade will be tested with IL-2 and interferon-a 2b, and with selective mutant BRAF inhibitors, which promote tumor T-cell infiltration. Our studies should have direct impact for current development of B7-H1/PD-1 blockade as a novel and promising approach for melanoma therapy.