ARID1A Mutations Are Associated with Increased Immune Activity in Gastrointestinal Cancer.

Lin Li,Xiaosheng Wang,Mengyuan Li,Zehang Jiang

doi:10.3390/cells8070678

Abstract

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch repair-deficient GI cancers. However, only a subset of cancer patients currently respond to immunotherapy. Thus, it is important to identify useful biomarkers for predicting cancer immunotherapy response. The tumor suppressor gene ARID1A has a high mutation rate in GI cancers and its deficiency is correlated with the microsatellite instability (MSI) genomic feature of cancer. We investigated the correlation between ARID1A mutations and tumor immunity using three GI cancer genomics datasets by the bioinformatic approach, and found that diverse antitumor immune signatures were more highly enriched in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers. The elevated immune activity in ARID1A-mutated GI cancers was associated with the higher tumor mutation burden and lower tumor aneuploidy level, as well as a higher proportion of MSI cancers in this GI cancer subtype. Moreover, we found that ARID1A-mutated GI cancers more highly expressed PD-L1 than ARID1A-wildtype GI cancers. The elevated antitumor immune signatures and PD-L1 expression could contribute to the more active immunotherapeutic responsiveness and better survival prognosis in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers in the immunotherapy setting, as evidenced in three cancer cohorts receiving immunotherapy. Thus, the ARID1A mutation could be a useful biomarker for identifying GI cancer patients responsive to immunotherapy.

Highlights

Gastrointestinal (GI) cancers are prevalent and account for a large number of cancer deaths globally [1]
We found that diverse immune signatures (CD8+ T cells, NK cells, immune cytolytic activity, activated CD4+ T cells, activated dendritic cells, MHC class I) consistently showed significantly higher enrichment levels in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers
We found that the ratios (CD8+ T cells versus CD4+ regulatory T cells, pro-inflammatory cytokines versus anti-inflammatory cytokines, and immune-promoting M1 macrophages versus immune-inhibiting M2 macrophages) were significantly higher in ARID1A-mutated GI cancers than in

Summary

Introduction

Gastrointestinal (GI) cancers are prevalent and account for a large number of cancer deaths globally [1]. Traditional treatment strategies for advanced GI cancers often have a limited therapeutic effect [2]. With the recent success of immunotherapy in treating various refractory malignancies [3,4,5,6], the immunotherapy strategy has become a viable approach for the therapy of advanced GI cancers [7]. A notable example is that two immune checkpoint inhibitors, pembrolizumab and nivolumab, have been clinically used for treating DNA mismatch repair-deficient GI cancers [7]. Despite these successes of cancer immunotherapy, a large proportion of cancer patients failed to respond to such therapy. Abundant evidence indicates that cancer immunotherapy response is associated with certain genetic or genomic features, such as PD-L1 expression [8], DNA mismatch repair deficiency [9], tumor mutation

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Results

Conclusion