LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

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 protein 15 (LRRC15)1–3. 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.

Fibroblast-expressed LRRC15 suppresses SARS-CoV-2 infection and controls antiviral and antifibrotic transcriptional programs

“…5a ). In the rat glia cell line C6 LRRC15 is mildly regulated in response to proinflammatory cytokines like IL1β, IL6, and TNFɑ 27 , and more recently TGFβ signalling has been linked to LRRC15 expression in cancer-associated fibroblasts 28, 29 . In human fibroblasts, we found IL1β, TNFɑ or IFNɣ do not induce detectable levels of LRRC15 (not shown), however TGFβ upregulates both LRRC15 ( Fig.…”

The importance of being CAFs (in cancer resistance to targeted therapies)

“…Similarly, McAndrews et al recently showed that genetic depletion of FAP+ CAFs increased PDAC survival, while of αSMA+ CAFs decreased it [30]. Always using transgenic mice models, Krishnamurty and colleagues selectively depleted the LRRC15+ CAF subpopulation in PDAC, and this was sufficient to significantly slow tumor growth and restore CD8+ T cell functions, increasing response to immunotherapy [31]. Since LRRC15+ CAF formation depends on TGFβ receptor 2 signaling [21], this opens the attractive possibility to use of TGFβ inhibitors to overcome CAF-mediated resistance to cancer immunotherapy.…”

“…Similarly, two distinct CAF populations with opposing roles in the progression and immune landscape were identified in PDAC, as, in this context, depletion of fibroblast activation protein (FAP)+ CAFs increased survival, while depletion of αSMA+ CAFs decreased survival [30]. Also the TGFβ-driven expression of the leucine-rich-repeat-containing protein 15 (LRRC15) in CAFs, characterizes a pro-tumorigenic CAF subpopulation, as the depletion of LRRC15+ CAFs in PDAC models slowed tumor growth and restored CD8+ T cell functions, increasing response to immunotherapy [31]. Why CAFs are so heterogeneous is not clear.…”

“…In this scenario, indiscriminate targeting of the whole CAF population could be ineffective or even harmful, thus making it necessary and urgent to identify reliable markers of the two subpopulations. In this context, two recent works offered great expectations [29,31]. Hutton et al, showed that the expression of a single protein, CD105, can easily and stably identify pro-tumorigenic CAFs, at least in PDAC [29].…”

“…However, as CD105 expression varies between cancer types [29], further studies are needed to elucidate whether CD105-negative CAFs are also a marker of immune response in tumors other than PDAC. Krishnamurty and colleagues identified the leucine-rich-repeat-containing protein 15 (LRRC15) as a promising, highly restricted marker of a subpopulation of CAFs with pro-tumorigenic, immunity-suppressing properties [31].…”