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Lung Cancer Treatment Response Linked to Cancer-Associated Fibroblast Cell Subtypes

NEW YORK – A team from the Massachusetts General Hospital, Novartis Institutes for BioMedical Research, and elsewhere has identified a handful of lung cancer-associated fibroblast subtypes with distinct clinical or biological features, including responses to tyrosine kinase inhibitor treatments.

"[W]e identify three major functional subtypes of [cancer-associated fibroblast (CAF)] that exhibit distinct impacts on treatments using EGFR and ALK TKIs," first author Haichuan Hu, an instructor in medicine with the MGH Cancer Center and Harvard Medical School, and his colleagues wrote in a study published in Cancer Cell on Thursday.

In the process, the team put together a CAF biobank that included samples from NSCLC cases with EGFR mutations or ALK fusions, offering clues to the fibroblast cell features that were shared and distinct in relation to the tumor cells.

"This large collection of CAFs allows us to adequately recapitulate a broad spectrum of NSCLC CAFs with diverse molecular features," the authors explained. "Here, we functionally characterize the landscape of NSCLC CAFs, reveal how they function differently, and demonstrate their potential clinical utilities."

For their analyses, the investigators first generated dozens of patient-derived fibroblast cultures using CAF cells isolated from non-small cell lung cancer biopsy samples. From there, they relied on a range of experiments — including RNA sequencing, RT-qPCR, immune, and secretome assays; and phenotypic, functional, mouse model, and targeted treatment response profiling — along with available single-cell and bulk RNA sequence data on NSCLC-associated fibroblasts to define three CAF subtypes with distinct biological and clinical characteristics.

In an email, Hu noted that such analyses may ultimately lead to personalized lung cancer treatment plans that take all the cell types in a lung tumor, including CAFs, into account.

"[W]e are able to demonstrate a link between an NSCLC patient's clinical response and the functional classification of CAFs from that patient's tumors," he and his co-authors wrote, "thus providing evidence supporting that this CAFs functional classification may have considerable value in future clinical management of cancer patients."

In the cluster of CAFs from subtype I, for example, the team saw higher-than-usual levels of hepatocyte growth factor (HGF) and fibroblast growth factor 7 (FGF7), along with protection of corresponding cancer cells against TKI treatment. Subtype II CAFs were also marked by enhanced FGF7 expression, but showed more moderate cancer protection than subtype I.

In those two subtypes, the researchers noted, combination treatments that include HGF-MET and/or FGFR pathway targeting may be effective, based on the new CAF data. On the other hand, CAFs in subtype III were linked to immune cell migration and tended to turn up in NSCLC patients with more promising clinical outcomes, hinting that immune-focused treatments may have promise in cases with these HGF-low, FGF7-low, and higher phospho-SMAD2 levels, which correspond to TGF-beta signaling.

"Apart from targeted therapy, we show that this CAF classification also has potential for evaluating patients in the context of immune therapy and may also aid in the research in other aspects of cancer biology," the authors wrote, adding that "[o]ur approach in exploring and exploiting fibroblast heterogeneity may also provide a valuable paradigm for these disciplines to further improve clinical patient management."

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