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Immunostimulatory cancer-associated fibroblast subpopulations can predict immunotherapy response in head and neck cancer

ABSTRACT: Purpose: Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment Experimental Design: We performed high dimensional single-cell RNA sequencing (scRNA-Seq) on four patient tumors pre- and post-treatment from a neoadjuvant trial of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients that were treated with the aPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-Seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes Results: Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFβ-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells Conclusions: Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. Additionally, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials

ORGANISM(S): Homo sapiens

PROVIDER: GSE195832 | GEO | 2022/03/16

REPOSITORIES: GEO

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Project description:To study of differential effect on cancer-associated fibroblasts of HNSCC, we have employed microarray expression profiling. The critical effect of the tumor microenvironment to caner progression is well recognized. Recent research suggests that the cancer-promoting properties of the tumor stroma may attributed to fibroblasts. However, little is known about fibroblasts that inhibit cancer progression. From the immunohistochemical analysis of cancer tissues from head and neck squamous cell carcinoma (HNSCC) patients, we divided cancer-associated fibroblast (CAF) into two groups depending on whether the boundary between epithelial cancer cells and the surrounding extracellular matrix (ECM) is clear and smooth or not. Therefore, we tried to evaluate whether there is a difference between these two CAFs in HNSCC progression. CAF was primary cultured, followed by co-culture with HNSCC cell to observe the effect on Matrigel invasion. The mRNA expression patterns between these two CAF groups were compared by DNA microarray analysis. FaDu cell and primary CAF from each group was co-transplanted into the oral mucosa of mice, and the tumorigenesis was compared. The CAF group (CAF-Promote, CAF-P) from cancer tissues which have unclear boundary between ECM and epithelial cancer cells showed a tendency to stimulate in vitro Matrigel invasion of HNSCC cell. On the contrary, the CAF group (CAF-Defense, CAF-D) from cancer tissues, which have clear boundary with epithelial cancer cell caused no remarkable increase of Matrigel invasion. In addition, CAF-D reduced the tumorigenicity of FaDu compared to CAF-P in the in vivo mice model. In DNA microarray analysis, COL3A1, COL6A6, COL25A1, and COL26A1 were particularly highly expressed in CAF-D group. In this study, these collagen proteins derived from cancer stroma were found to have a function of inhibiting the progression of HNSCC. It is expected to provide important information for predicting the prognosis of HNSCC and development of drug target in the future.

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Immunostimulatory cancer-associated fibroblast subpopulations can predict immunotherapy response in head and neck cancer

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