Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy

Abstract

Chromatin regulation involves four subfamilies composed of ATP-dependent multifunctional protein complexes that remodel the way DNA is packaged. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex subfamily mediates nucleosome reorganization and hence activation/repression of critical genes. The SWI/SNF complex is composed of the BRG-/BRM-associated factor and Polybromo-associated BAF complexes, which in turn have multiple subunits. Significantly, ~20% of malignancies harbor alterations in >1 of these subunits, making the genes encoding SWI/SNF family members among the most vulnerable to genomic aberrations in cancer. ARID1A is the largest subunit of the SWI/SNF complex and is altered in ~40%–50% of ovarian clear cell cancers and ~15%–30% of cholangiocarcinomas, in addition to a variety of other malignancies. Importantly, outcome was improved after immune checkpoint blockade (ICB) in patients with ARID1A-altered versuss wild-type tumors, and this result was independent of microsatellite instability or tumor mutational burden. Another subunit—PBRM1—is mutated in ~40% of clear cell renal cell carcinomas and ~12% of cholangiocarcinomas; there are contradictory reports regarding ICB responsiveness. Two other SWI/SNF subunits of interest are SMARCA4 and SMARCB1. SMARCA4 loss is the hallmark of small cell carcinoma of the ovary hypercalcemic type (and is found in a variety of other malignancies); SMARCA4 germline alterations lead to rhabdoid tumor predisposition syndrome-2; SMARCB1 germline alterations, rhabdoid tumor predisposition syndrome-1. Remarkable, although anecdotal, responses to ICB have been reported in both SMARCA4-aberrant and SMARCB1-aberrant advanced cancers. This review focuses on the role that SWI/SNF chromatin remodeling subunits play in carcinogenesis, the immune microenvironment, and in immunotherapy responsiveness.

The immune response-related genomic alterations in patients with malignant melanoma

“…PBRM1 encodes a subunit of the SWI/SNF complex, which is important in chromatin remodeling. [46] PBRM1 alterations are considered a biomarker predicting response to immunotherapy in clear cell renal cell carcinoma, [47,48] similar to what has been seen in our series. In contrast, investigation showed that PBRM1 mutations were associated with fewer immune infiltrates and lower response rates to immunotherapy.…”

High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome

“… 32 Other biomarkers may also predict response to immunotherapy, including but not limited to the presence of aberrant chromatin remodeling genes, T-cell repertoire, and expression of PD-1 on tumor-infiltrating lymphocytes. 33 – 35 …”

SMARCB1 as a potential indicator of the prognosis of oral squamous cell carcinoma

“…Chromatin remodeling elements are a group of proteins that redesign the way DNA architecture is bundled for the sake of facilitating the access to the condensed genomic DNA by the transcription machinery; therefore regulating gene expression. Chromatin's main purpose is thus to collect long DNA molecules into more compact, yet complicated structures (28) . In addition, nucleosomes play a main role in controlling gene expression as they prevent the binding of transcription factors, which are the key proteins in control of activating or inactivating the expression of specific genes.…”