Enhancing immune therapy in pancreatic cancer by targeting IL-6

胰腺导管腺癌(PDAC)伴有严重的全身免疫抑制。 使这种疾病对免疫治疗无反应。PDAC的一个特点是密集的间质，包括 这些被激活的成纤维细胞被称为“胰腺星状细胞”(PSC)，分布在每个肿瘤周围。尽管这些 基质细胞产生许多可能支持肿瘤生长的因素，最近的出版物也表明 间质在防止转移中的相互矛盾的作用。更令人惊讶的是观察到的 从PDAC的遗传模型中去除PSC可以提高免疫治疗的效果。这些数据 强调该提案的重要性，以及人们对两者之间错综复杂的相互作用知之甚少 间质和免疫细胞存在于肿瘤微环境中。这些结果还表明， 针对肿瘤的免疫反应受到PSC的抑制，靶向间质中的关键通路可能 增强免疫疗法的疗效。根据这些观察，我们小组最近发表的一份报告 证明患者来源的PSC分泌可溶性因子促进髓系来源的抑制细胞 (MDSC)分化。详细的分析表明，这个过程需要STAT3信号，并且 是由于PSC分泌了大量的白介素6(IL-6)。这些数据显示了一种新的作用 间质PSC是PDAC中抑制免疫的因子的来源，并激发了我们对 靶向IL-6以加强免疫治疗。我们的初步数据显示，体内注射抗体 (AB)靶向白介素6(IL-6)和PD-L1可抑制皮下和体内的肿瘤进展， 突变的KRAS驱动的PDAC模型。我们还证明了这种治疗组合的结果是 T细胞在胰腺肿瘤中的渗透，以及这些肿瘤中PSC水平的降低。我们 假设间质IL-6是促进PDAC免疫抑制的主要屏障，并且它 可以有针对性地增强对免疫疗法的反应。这项提案将解决三个具体问题 目标。首先，我们将确定联合阻断IL-6和PD-L1产生抗肿瘤的机制 PDAC的疗效，重点是T细胞和MDSC的表型和功能特性(目标1)。相对的 PD-L1在肿瘤或宿主组织上的表达在调节该治疗效果方面的重要性将是 调查过了。接下来，我们将确定基于紫杉烷的化疗是否增强了IL-6和PD-L1的疗效 封锁原生的、突变的KRAS驱动的PDAC模型(目标2)。最后，我们将使用DUAL 重组酶系统(FLP-FRT和Cre-loxP)建立KRAS突变驱动的自发性小鼠模型 PDAC和IL-6缺失的成纤维细胞和原发患者PSC明确基质IL-6的促进作用 胰腺癌进展和免疫抑制(目标3)。这项建议将增进我们的了解 间质如何影响PDAC的致癌和免疫抑制。这些研究的数据还包括 以IL-6为靶点的单抗与免疫治疗相结合，有可能产生近期的临床影响。

Pancreatic ductal adenocarcinoma (PDAC) is accompanied by profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. One hallmark of PDAC is the dense stroma consisting of activated fibroblasts termed `pancreatic stellate cells' (PSC) that surround each tumor. Although these stromal cells produce numerous factors that may support tumor growth, recent publications also suggest a contradictory role for the stroma in protecting against metastasis. Even more surprising was the observation that depletion of PSC from genetic models of PDAC led to improved efficacy of immunotherapy. These data highlight the significance of the proposal, and how little is known regarding the intricate interactions between stroma and immune cells present within the tumor microenvironment. These results also suggest that the immune response against tumors is restrained by PSC, and that targeting key pathways in the stroma may augment the efficacy of immunotherapy. In line with these observations, a recent publication from our group demonstrated that patient-derived PSC secrete soluble factors to promote myeloid-derived suppressor cell (MDSC) differentiation. Detailed analyses revealed that STAT3 signaling was required for this process, and was due to copious amounts of interleukin-6 (IL-6) secreted from PSC. These data demonstrated a novel role for stromal PSC as a source of factors that suppress immunity in PDAC, and have fueled our interest in targeting IL-6 to enhance immunotherapy. Our preliminary data show that in vivo administration of antibodies (Ab) targeting interleukin-6 (IL-6) and PD-L1 limit tumor progression in both subcutaneous, and autochthonous, mutant KRas-driven models of PDAC. We also demonstrate this treatment combination results in increased infiltration of T cells into pancreatic tumors, and reduced levels of PSC within these same tumors. We hypothesize that stromal IL-6 is a major barrier promoting immune suppression in PDAC, and that it can be targeted to augment the response to immunotherapy. This proposal will address three Specific Aims. First, we will determine the mechanisms by which combined blockade of IL-6 and PD-L1 elicits antitumor efficacy in PDAC, focusing on phenotypic and functional properties of T cells and MDSC (Aim 1). The relative importance of PD-L1 expression on the tumor or host tissues in mediating efficacy of this treatment will be investigated. Next, we will determine if taxane-based chemotherapy augments the efficacy of IL-6 and PD-L1 blockade in autochthonous, mutant KRas-driven PDAC models (Aim 2). Finally, we will use a dual recombinase system (Flp-FRT and Cre-loxP) to develop mice with spontaneously arising, mutant KRas-driven PDAC and IL-6 deleted fibroblasts, and primary patient PSC to define the role of stromal IL-6 in promoting pancreatic cancer progression and immune suppression (Aim 3). This proposal will enhance our understanding of how the stroma influences carcinogenesis and immune suppression in PDAC. Data from these studies also have potential for near-term clinical impact with Ab targeting IL-6 in combination with immunotherapy.