Role for TbetaRIII Shedding in the Tumor Microenvironment

转化生长因子-β(转化生长因子-β)超家族配体抑癌促癌作用 通过仍未完全确定的机制取得进展。我们已经证明了III型的损失 转化生长因子-β受体(T-βRIII)在人类肿瘤中的表达是一种常见事件。TβRIII抑制癌症 进展，部分是通过胞外结构域脱落产生可溶性TβRIII(StβRIII)，它具有 在整个肿瘤微环境(TME)中调节信号的可能性。在恢复TβRIII时 在癌细胞中的表达和/或STβRIII治疗产生免疫耐受的TME，其机制和 T-βRIII和ST-βRIII在调节TME中的相对贡献及其在癌症中的作用 癌症的发生和发展尚未确定。在这里，我们定义了结构决定因素 在调节TβRIII脱落方面发挥作用，这使我们能够创造：i)TβRIII超级脱落器(TβRIII-SS)和ii) TβRIII型非脱毛器(TβRIII型∆Share)，建立相应的小鼠模型。我们已经证明了 中性粒细胞可能参与调节T-βRIII的脱落。基于这些结果，我们假设中性粒细胞介导的 乳腺癌和黑色素瘤中TβRIII缺失/脱落/降解增加转化生长因子-β超家族信号 TME通过在TME中丢失STβRIII，促进癌症进展，部分是通过产生免疫耐受 我也是。我们进一步假设，表达ST-βRIII或功能类似物抑制转化生长因子-β信号转导。 TME将绕过耐药机制，提高当前免疫疗法的疗效 接近了。我们提出了三个具体目标。目标1：中性粒细胞和丝氨酸的作用机制 组织蛋白酶G和中性粒细胞弹性蛋白酶介导T-βRIII的脱落/降解 将探索TME，包括定义TβRIII介导脱落的结构决定因素。目标2：我们将 确定TβRIII/STβRIII的丢失是否增加了TME中的转化生长因子-β超家族信号以创建 免疫耐受的TME可促进癌症的启动或进展。目标3：我们将定义是否表达 STβRIII或功能类似物与目前的免疫治疗方法相结合，将导致 乳腺癌和黑色素瘤的更有效治疗以及血清STβRIII或转化生长因子-β1水平 具有预测生物标志物的功能。这些研究将有助于确定胞外结构域的生物学功能 在TME的背景下剥离TβRIII，为理解转化生长因子-β的作用提供广泛的影响 超家族信号在人类癌症发生和发展中的作用，同时为 将抗转化生长因子-β信号治疗与现有的免疫治疗方法相结合。

Transforming growth factor-β (TGF-β) superfamily ligands function to suppress then promote cancer progression through mechanisms that remain to be fully defined. We have demonstrated that loss of type III TGF-β receptor (TβRIII) expression is a frequent event in human cancers. TβRIII suppresses cancer progression, in part, through ectodomain shedding that generates a soluble TβRIII (sTβRIII), which has the potential to regulate signaling throughout the tumor microenvironment (TME). While restoring TβRIII expression in cancer cells and/or sTβRIII treatment created an immunotolerant TME, the mechanisms and relative contribution of TβRIII and sTβRIII in regulating the TME, as well as their respective roles in cancer initiation and cancer progression have not been established. Here we defined the structural determinants operant in regulating TβRIII shedding, which enabled us to create: i) a TβRIII super-shedder (TβRIII-SS) and ii) a TβRIII non-shedder (TβRIII∆shed), with corresponding murine models. We have demonstrated that neutrophils may regulate TβRIII shedding. Based on these results, we hypothesize that neutrophil-mediated TβRIII loss/shedding/degradation in breast cancer and melanoma increases TGF-β superfamily signaling in the TME via loss of sTβRIII in the TME, promoting cancer progression, in part, by creating an immunotolerant TME. We further hypothesize that expressing sTβRIII or functional analogues to suppress TGF-β signaling in the TME will circumvent a mechanism of resistance and increase the efficacy of current immunotherapy approaches. We propose three Specific Aims. Aim 1: The mechanism by which neutrophils and the serine proteases, cathepsin G (CTSG) and neutrophil elastase (ELANE), mediate TβRIII shedding/degradation in the TME will be explored including defining structural determinants on TβRIII mediating shedding. Aim 2: We will define whether loss of TβRIII/sTβRIII increases TGF-β superfamily signaling in the TME to create an immunotolerant TME to promote cancer initiation or progression. Aim 3: We will define whether expressing sTβRIII or functional analogues in the TME in conjunction with current immunotherapy approaches will result in more effective therapies for breast cancer and melanoma and whether serum sTβRIII or TGF-β1 levels function as predictive biomarkers. These studies will help define the biological functions of ectodomain shedding of TβRIII in the context of the TME, providing broad impact on understanding the role of TGF-β superfamily signaling in human cancer initiation and progression, while providing proof of principle for combining anti-TGF-β signaling therapy with current immunotherapy approaches.