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 protein 15 (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 receptor type 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⁺ T cells 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⁺ T cell 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.

最近对小鼠和人类癌症的单细胞研究已经确定了肌成纤维细胞群的出现，这些肌成纤维细胞群特别以高度受限的富含亮氨酸重复蛋白 15 (LRRC15) ^1,2,3为标志。然而，作为 LRRC15 ⁺癌症相关成纤维细胞 (CAF) 发育基础的分子信号及其对抗肿瘤免疫的直接影响尚不清楚。在胰腺癌小鼠模型中，我们提供了体内遗传证据，证明健康皮桥蛋白 + 通用成纤维细胞中的 TGFβ 受体 2 型信号传导^对于癌症相关 LRRC15 ^{+的发展至关重要}肌成纤维细胞。该轴还主要驱动人类癌症中的成纤维细胞谱系多样性。使用新开发的 Lrrc15-白喉毒素受体敲入小鼠选择性地耗尽 LRRC15 ⁺ CAF，我们表明该种群的耗尽显着降低了肿瘤成纤维细胞的总含量。此外，CAF 成分针对通用成纤维细胞进行了重新校准。^{这减轻了对肿瘤浸润性 CD8 +} T 细胞的直接抑制，以增强其效应功能，并增强肿瘤消退以响应抗 PDL1 免疫检查点阻断。总的来说，这些发现表明 TGFβ 依赖性 LRRC15 ⁺CAF 决定肿瘤-成纤维细胞设定点以促进肿瘤生长。这些细胞还直接抑制 CD8 ⁺ T 细胞功能并限制对检查点封锁的反应。开发通过减少促病 LRRC15 ⁺肌成纤维细胞的数量来恢复稳态成纤维细胞设定点的治疗方法可能会提高患者的存活率和对免疫疗法的反应。