NEW YORK (GenomeWeb) – Scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have published details of a study in which they identified over 100 new genetic regions that affect individuals' immune response to cancer and that they believe provide new leads for cancer immunotherapy development.
Specifically, "by analyzing a large public genomic database, we found 122 potential immune response drivers — genetic regions in which mutations correlate with the presence or absence of immune cells infiltrating the tumors," Eduard Porta-Pardo, a postdoctoral fellow at SBP and one of the authors on the study, said in a statement. Full details of the study are described in a Cancer Immunology Research paper that was published earlier this month.
According to the researchers, their findings "expand the catalog of potential cancer immunity drivers" and offer opportunities to develop a much broader pool of immunotherapies for patients. Immunotherapies work by boosting the body's natural defenses to fight cancers and have been successfully used to treat tumors and prevent recurrence even in more advanced cases of the disease. However, they don't work in all cases as some cancers have mechanisms for hiding from the immune system or for blocking immune cells from entering tumors.
"In order to develop immunotherapies that are effective for a wide range of cancers, we need to know a lot more about how the immune system interacts with tumors," Adam Godzik, professor and director of Sanford Burnham's bioinformatics and structural biology program and senior author of the study, said in a statement.
Godzik told GenomeWeb this week that much of the current research into how tumors hide focuses on the over-expression of so-called checkpoint inhibitors in cancer cells. But this pattern is observed in only about 20 percent of cancers, he said. In the remaining 80 percent of cases, this pattern of overexpression is not present and treatments that block these inhibitors don't work, indicating that other genetic changes drive these cancers' interactions with the immune system. "That's basically what the paper is about," he said. "We are trying to look beyond checkpoint inhibitors and find other mechanisms by which cancer cells are able to evade the immune system."
As explained in the paper, the researchers analyzed 5,164 tumor samples from 21 different cancer types from the Cancer Genome Atlas datasets. They looked for protein domains within these samples that had a mutation status that was correlated with the presence of "immune infiltrate" — the presence of immune cells within the cancer tissue. For the study, they used a statistical tool that they developed called domainXplorer, which is designed to look for correlations between phenotypes such as immune response and mutation patterns in individual protein regions. It is an expanded version of an earlier method that the researchers developed called e-Driver. That method is described in a paper published in Bioinformatics in 2014.
According to the paper, the researchers identified 122 protein regions that had statistically significant correlations between mutations and immune response, some of which were in proteins involved in immune-response related pathways. They assessed three of these protein domains and their associations with immune response and found, for example, that patients with mutations in the hybrid-binding domain of the POLR3B protein have more immune cell infiltration than both POLR3B wild-type patients as well as patients with mutations in other POLR3B domains. They also identified mutations in a region of the CDH11 protein that interacts with CTNNB1 that are correlated with more immune infiltrate. Furthermore, "in several cases, we show that mutations within the same protein can be associated with more or less immune cell infiltration, depending on the specific domain mutated," the authors wrote. For example, mutations in clamp region of the POLR3B protein have less immune cell infiltration, they wrote.
For their next steps, the Sanford Burnham researchers plan to use domainXplorer to search for genetic regions that correlate with the levels of specific immune cell types in tumors. As part of this next phase of research, they will also re-run their analysis on a larger cohort of TCGA to see if their predictions hold with twice as much data as was used for the current study, Godzik told GenomeWeb.
He and his colleagues have started some preliminary discussions with researchers at Sanford Burnham about potentially testing some of the immune response drivers that their study identified, but these talks are still very much in the early stages, he said. They are also open to collaborating with researchers from other institutions and industry who are interested in further exploring these immune drivers, he added.
In addition, Godzik and Porta-Pardo hope to partner with other research groups to repeat their analysis in the context of specific cancers in order to identify unique genetic drivers and mechanisms that influence immune response in specific subtypes, Godzik said.