NEW YORK (GenomeWeb) – Research presented in two related studies suggest mutations affecting the SWI/SNF chromatin remodeling complex can lead to more robust anti-tumor immune T cell activity and enhanced cancer vulnerability to immune checkpoint blockade treatments.
In a Science paper published online today, a Dana-Farber Cancer Institute- and Broad Institute-led team described findings from an exome sequencing-based analysis of metastatic clear cell renal cell carcinoma (ccRCC), aimed at uncovering genomic contributors to anti-PD-1 checkpoint blockade immunotherapy response.
Unlike many of the cancer types known for checkpoint blockade immunotherapy response, the authors explained, T cells and other immune contributors often infiltrate ccRCC tumors, even those containing relatively few of the mutations that help flag tumors as foreign. Consequently, they suspected that "distinct molecular mechanisms underlie the immunologically active tumor microenvironment and responsiveness to immune checkpoint therapy in patients with ccRCC."
The team 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.
The researchers 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."
For a related study, also appearing in Science, researchers from Dana-Farber, the Broad, and Harvard Medical School used CRISPR-Cas9-based gene editing to screen for mutations that made melanoma more vulnerable to T cells in a mouse model of the disease.
"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.
With that in mind, the team did CRISPR-Cas9 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.
Based on findings from such analyses — together with previously published data — the authors suggested that "[h]uman tumors with inactivating mutations in PBRM1, ARID2, and BRD7 may therefore be more sensitive to PD-1 blockade as well as other forms of immunotherapy in which cytotoxic T cells serve as the main effector mechanism, including cancer vaccines and adoptive T cell therapies."