小柯机器人

美国基因泰克公司Shannon J. Turley、Sören Müller等研究人员合作发现，LRRC15⁺肌成纤维细胞决定抑制肿瘤免疫的基质设定值。该项研究成果于2022年9月28日在线发表在《自然》杂志上。

据研究人员介绍，最近对小鼠和人类癌症的单细胞研究发现，出现了一个由高度限制性的富含亮氨酸重复蛋白15（LRRC15）特别标记的肌成纤维细胞群。然而，支撑LRRC15⁺癌症相关成纤维细胞（CAF）发展的分子信号以及它们对抗肿瘤免疫的直接影响还没有被描述出来。

在胰腺癌的小鼠模型中，研究人员提供了体内遗传学证据，表明健康的皮连蛋白⁺通用成纤维细胞中的TGFβ受体2型信号对于癌症相关的LRRC15⁺肌成纤维细胞的发展至关重要。这一信号轴也主要驱动人类癌症中的成纤维细胞系多样性。使用新开发的Lrrc15-白喉毒素受体敲入小鼠选择性地耗竭LRRC15⁺CAF，研究人员表明耗竭这一群体明显地减少了肿瘤纤维母细胞的总含量。此外，CAF的组成被重新调整为通用成纤维细胞。这解除了对肿瘤浸润性CD8⁺T细胞的直接抑制来增强其效应功能，并增强了对抗PDL1免疫检查点阻断的肿瘤消退。

总之，这些发现表明，TGFβ依赖性的LRRC15⁺CAF决定了肿瘤-成纤维细胞的设定点，进而促进肿瘤的生长。这些细胞还直接抑制CD8⁺T细胞功能，并限制对检查点阻断的反应性。通过减少促进疾病的LRRC15⁺肌成纤维细胞的数量来恢复平衡的成纤维细胞设定点的疗法开发可能会改善患者的生存和对免疫疗法的反应。

附：英文原文

Title: LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

Author: Krishnamurty, Akshay T., Shyer, Justin A., Thai, Minh, Gandham, Vineela, Buechler, Matthew B., Yang, Yeqing Angela, Pradhan, Rachana N., Wang, Amber W., Sanchez, Patricia L., Qu, Yan, Breart, Beatrice, Chalouni, Ccile, Dunlap, Debra, Ziai, James, Elstrott, Justin, Zacharias, Neelie, Mao, Weiguang, Rowntree, Rebecca K., Sadowsky, Jack, Lewis, Gail D., Pillow, Thomas H., Nabet, Barzin Y., Banchereau, Romain, Tam, Lucinda, Caothien, Roger, Bacarro, Natasha, Roose-Girma, Merone, Modrusan, Zora, Mariathasan, Sanjeev, Mller, Sren, Turley, Shannon J.

Issue&Volume: 2022-09-28

Abstract: Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein15 (LRRC15)1,2,3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptortype 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ Tcells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ Tcell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.

DOI: 10.1038/s41586-022-05272-1

Source: https://www.nature.com/articles/s41586-022-05272-1

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