Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 27-30, 2018; Miami Beach, FL Imprime PGG (Imprime), an intravenously administered, soluble, yeast β-1,3/1,6 glucan, is currently in clinical development with tumor-targeting, antiangiogenic and checkpoint inhibitor antibodies. The fundamental mechanistic rationale for these different therapeutic combinations is that Imprime, a pathogen-associated molecular pattern (PAMP), primes innate immune effector functions to drive a coordinated anticancer immune response. Previous preclinical mechanistic work has shown that Imprime activates the functionalities of monocytes, macrophages, and dendritic cells (cells that principally influence the TME), eliciting a tumor microenvironment (TME) that activates T cell-dependent antitumor immunity. Studies have shown that mature neutrophils and immature myeloid-derived suppressor cells (PMN-MDSC) accumulate, like other myeloid cells, in the tumor and play a role in establishing the immunosuppressive TME and impair T-cell immunity. Herein, we provide evidence that Imprime treatment reorients neutrophil function, enlisting these cells in anticancer immunity. To date, exploration of the effect of Imprime on neutrophils has evaluated direct neutrophil-mediated tumor killing. In this study, we further explored the impact of Imprime treatment on mature neutrophils and immature PMN-MDSC (i.e., the Ly6Ghigh population) in both tumor-free and tumor-bearing mice. In tumor-free C57BL/6 mice, Imprime mobilized Ly6Ghigh cells into the blood, spleen, and skin draining lymph nodes (sdLNs). The increase of these cells in the sdLN coincided with increased levels of CCL2, CCL3, CCL4, CXCL1 and CXCL10, chemokines important for the mobilization of myeloid cells. In the H1299 lung cancer xenograft model, the addition of Imprime to bevacizumab enhanced CD86 expression on Ly6Ghigh cells in both spleen and tumor tissues when compared to bevacizumab alone, indicating that these cells could play a role in T-cell activation. We therefore assessed the effect of Imprime in MC-38, syngeneic tumor model, shown to be sensitive to Imprime in combination with immune checkpoint inhibitor antiboides (i.e., anti-PD1 and PD-L1). Consistent with our earlier findings, Imprime and Imprime + anti-PD-1 treatments significantly increased the percentage of Ly6Ghigh cells in the spleen and the tumor compared to the vehicle alone. The Ly6Ghigh cells in both the spleen and TME showed increased expression of CD86, MHCII and PD-L1. The enriched PMN-MDSC (~60-70% Ly6Ghigh) from the spleens of Imprime-treated mice were significantly less suppressive to CD3/CD28-mediated proliferation of CD3+ splenocytes. Collectively, these data show that neutrophils have a role in Imprime-mediated remodeling of the immunosuppressive TME, driving a more conducive environment to T-cell immunity. The effects of Imprime on peripheral and tumor-associated neutrophils in cancer patients are currently being explored in phase 2 clinical trials employing the combination of Imprime and anti-PD1 antibody, pembrolizumab. Citation Format: Adria L. Bykowski Jonas, Anissa S.H. Chan, Nadine C. Ottoson, Xiaohong Qui, Keith Gordon, Mark Uhlik, Jeremy Graff, Nandita Bose. Treatment with Imprime PGG, a soluble yeast β-glucan PAMP, induces trafficking of activated Ly6Ghigh cells to secondary lymphoid organs and tumor and facilitates immune activation within the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A01.

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摘要A01：使用可溶性酵母β-葡聚糖PAMP Imprime PGG进行处理，可诱导活化的Ly6Ghigh细胞向次级淋巴器官和肿瘤的转运，并促进肿瘤微环境中的免疫活化。

摘要：AACR肿瘤免疫学和免疫疗法特别会议；2018年11月27日至30日; 佛罗里达州迈阿密海滩Imprime PGG（Imprime）是一种静脉给药的可溶酵母β-1,3/ 1,6葡聚糖，目前正处于临床开发中，具有靶向肿瘤，抗血管生成和检查点抑制剂的抗体。这些不同治疗组合的基本机械原理是，Imprime是一种病原体相关的分子模式（PAMP），可引发先天性免疫效应子功能来驱动协同的抗癌免疫反应。先前的临床前机制研究表明，Immrime激活单核细胞，巨噬细胞和树突状细胞（主要影响TME的细胞）的功能，从而引发激活T细胞依赖性抗肿瘤免疫力的肿瘤微环境（TME）。研究表明，与其他髓样细胞一样，成熟的中性粒细胞和未成熟的髓样来源的抑制细胞（PMN-MDSC）在肿瘤中蓄积，并在建立免疫抑制性TME和损害T细胞免疫性方面发挥作用。在这里，我们提供证据表明Imprime治疗可重新定向中性粒细胞功能，使这些细胞具有抗癌免疫性。迄今为止，探索Imprime对嗜中性粒细胞的作用已评估了直接嗜中性粒细胞介导的肿瘤杀伤。在这项研究中，我们进一步探讨了Imprime治疗对无肿瘤小鼠和荷瘤小鼠中成熟嗜中性粒细胞和未成熟PMN-MDSC（即Ly6Ghigh群体）的影响。在无肿瘤的C57BL / 6小鼠中，Imprime将Ly6Ghigh细胞动员到血液，脾脏和皮肤引流淋巴结（sdLNs）中。这些细胞在sdLN中的增加与CCL2，CCL3，CCL4，CXCL1和CXCL10（趋化因子对骨髓细胞的动员重要）水平的升高相吻合。在H1299肺癌异种移植模型中，与单独贝伐单抗相比，在贝伐单抗中添加Imprime增强了脾脏和肿瘤组织Ly6Ghigh细胞上CD86的表达，表明这些细胞可能在T细胞活化中起作用。因此，我们结合免疫检查点抑制剂抗体（即抗PD1和PD-L1）评估了Imprime在同质肿瘤模型MC-38中的作用，该模型对Imprime敏感。与我们先前的发现一致，与单独使用赋形剂相比，Imprime和Imprime +抗PD-1治疗显着增加了脾脏和肿瘤中Ly6Ghigh细胞的百分比。脾脏和TME中的Ly6Ghigh细胞均显示CD86，MHCII和PD-L1的表达增加。Imprime处理的小鼠脾脏中富集的PMN-MDSC（〜60-70％Ly6Ghigh）对CD3 / CD28介导的CD3 +脾细胞增殖的抑制作用明显较低。总体而言，这些数据表明中性粒细胞在免疫抑制TME的Imprime介导的重塑中发挥作用，从而为T细胞免疫创造了更有利的环境。目前正在结合Imprime和抗PD1抗体Pembrolizumab进行的2期临床试验中，研究Imprime对癌症患者外周和与肿瘤相关的中性粒细胞的影响。引文格式：Adria L. Bykowski Jonas，Anissa SH Chan，Nadine C.Ottoson，Xiaohong Qui，Keith Gordon，Mark Uhlik，Jeremy Graff，Nandita Bose。用Imprime PGG治疗，可溶性酵母β-葡聚糖PAMP诱导活化的Ly6Ghigh细胞向次级淋巴器官和肿瘤的运输，并促进肿瘤微环境内的免疫活化[摘要]。在：AACR肿瘤免疫学和免疫疗法特别会议论文集；2018年11月27日至30日; 佛罗里达迈阿密海滩。费城（PA）：AACR；Cancer Immunol Res 2020; 8（4增刊）：摘要编号A01。