Despite its encouraging successes, cancer immunotherapy mostly fails against cancer. If cancer immunotherapy is to succeed more widely, its failures will have to be scrutinized for mechanisms of resistance—mechanisms that can then be recognized as drug targets.
One mechanism of cancer resistance has been uncovered by two recent studies—one a preclinical study, the other a clinical study of patients with kidney cancer. Both studies converged on the chromatin remodeling complex. This class of genes, the studies determined, also influences sensitivity to an immunotherapy called checkpoint inhibition.
In the preclinical study, a group of scientists based at the Dana-Farber Cancer Institute used CRISPR technology to screen the genetics of a mouse melanoma cell line that was resistant to immune checkpoint inhibitors. These scientists, led by Kai Wucherpfennig, M.D., Ph.D., and Shirley Liu, Ph.D., found that many genes could, upon deactivation, enhance the sensitivity of the tumor cells to drugs. The Dana-Farber team focused on three genes—Pbrm1, Arid2, and Brd7—which encode proteins that regulate how tightly DNA is packaged in cells. More specifically, these genes encode components of the PBAF form of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex.
Additional details appeared January 4 in the journal Science, in an article entitled “A Major Chromatin Regulator Determines Resistance of Tumor Cells to T Cell–Mediated Killing.” The article describes how loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells.
“Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated,” the article’s authors noted. “In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.”
In the other study, which focused on patients with a certain form of kidney cancer called clear-cell renal cell carcinoma (ccRCC), scientists from Dana-Farber and the Broad Institute of MIT and Harvard also homed in on genes of the chromatin remodeling complex.
The scientific team, led by Dana-Farber’s Toni Choueiri, M.D., and the Broad’s Eliezer Van Allen, M.D., sought an explanation for why some patients with ccRCC gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the programmed cell death protein 1 (PD-1) checkpoint, while other patients don't.
The scientists' were curious to learn why ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small-cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive “neoantigens” that help the patient's immune system recognize and attack tumors and make the cancer cells' “microenvironment” hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients, even with advanced metastatic disease, respond well to immunotherapy.
To explore how ccRCC responds to immunotherapy, the scientists sequenced tumor samples and healthy tissue for 35 patients to find mutations unique to the tumor cells, mutations that might correlate with resistance or sensitivity. (The immunotherapy considered in this study was the checkpoint blocker nivolumab, or Opdivo®.)
Results from this work also appeared January 4 in Science, in an article entitled “Genomic Correlates of Response to Immune Checkpoint Therapies in Clear Cell Renal Cell Carcinoma.” This article indicates that DNA sequencing identified seven recurrently mutated genes. But of these genes, PBRM1 was the only one in which loss-of-function mutations correlated with a better response to immunotherapy.
“We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies,” wrote the article’s authors. “Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways.”
While the finding does 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.”
Implications for future immunotherapy research were also considered by the authors of the preclinical study. They commented that the protein products of the genes they identified “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell-mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”