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Mutations in Chromatin Remodelling Genes Could Play Key Role in Cancer Immunotherapy Resistance

An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors. Both studies converged on the chromatin remodeling complex. This class of genes, the studies determined, also influences sensitivity to an immunotherapy called checkpoint inhibition.

One report focuses on on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard. The second identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by scientists of Dana-Farber.

The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.

The first group set out to find why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit — sometimes durable — from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.

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Therefore they sequenced protein-coding sequences captured from matched tumor and normal samples from 35 individuals with ccRCC. Along with information on patients’ response to the anti-PD-1 drug nivolumab, the exome sequences led to recurrent mutations in the chromatin remodeling complex gene PBRM1 in individuals who appeared to benefit from checkpoint blockade treatment.

Then they verified those findings using targeted or exome sequence data for 63 more metastatic ccRCC cases treated with anti-PD-L1 therapy alone or in combination with CTLA4-targeting treatment. That effect seemed to extend to cases with intermediate immunotherapy response, they noted.

Gene set enrichment analyses, expression profiling, and follow up studies in mice supported the notion that tumors with mutations in PBRM1 or other components of the PBAF chromatin remodeling subtype are marked by enhanced immunotherapy response, along with tumor hypoxia, enhanced JAK/STAT signaling, and immune shifts.

“[W]e have shown that patients with metastatic ccRCC harboring truncating mutations in PBRM1 experienced increased clinical benefit from immune checkpoint therapy,” corresponding authors Eliezer Van Allen and Toni Choueiri, medical oncology researchers at the Dana-Farber Cancer Institute, and their colleagues wrote. “This may be due to distinct immune-related gene expression profiles in PBRM1-mutant or PBAF-deficient tumor cells compared to their PBAF-intact counterparts, as shown by RNA-seq analyses in this study, though further in vivo studies will be needed to further explore these findings.

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The other team came at the issue from a different angle- they sifted through the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.

We propose that targeting of tumor cell-intrinsic resistance mechanisms to T cell-mediated cytotoxicity will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy,” corresponding authors Kai Wucherpfennig and Shirley Liu of Dana-Farber, and their colleagues, wrote.

The team used CRISPR editing in a PD-1- and CTLA-4 checkpoint blockade-resistant mouse melanoma cell line called B16F10, using a genome-wide guide RNA library to systematically remove individual genes and search for mutations that altered response to T cells with relatively low- or high- T-cell receptor affinity. Along with immunotherapy resistance-related mutations in immune genes from major histocompatibility class I or interferon gamma pathways, inactivation of chromatin remodeling genes such as PBRM1 and ARID2 appeared to be immunotherapy-sensitizing — a pattern supported by available RNA sequence data from human melanoma cases hinting at enhanced CD8 T cell activity in cancers with lower-than-usual expression of PBRM1 and ARID2.

While the findings do not directly lead to a test for immunotherapy response yet, Dr. Choueiri said, “We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations.

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