A study from MIT reveals a new reason why checkpoint inhibitors may not work on some tumors.
In mice, a tumor’s mutation diversity was much more useful for predicting the treatment’s effectiveness than measuring the overall number of mutations, which was previously thought to be key. The more heterogeneous tumors are, the less effective checkpoint inhibitors are, the team’s research showed. Their paper appeared last week in Nature Genetics.
“This work makes clear the role of genetic heterogeneity in cancer in determining the effectiveness of these treatments,” says Tyler Jacks, a senior author of the paper and a professor of Biology and member of MIT’s Koch Institute for Cancer Research.
Immunotherapies, such as checkpoint inhibitors, have revolutionized cancer care because they can sometimes produce cures. They now make up a market is estimated will be worth almost $130 billion by 2030. But these treatments only work in about 20% to 30% of patients, so figuring out who they work in and why is a high stakes endeavor.
Immune checkpoint blockade, provided by checkpoint inhibitors, take the brakes off the body’s T cell response, stimulating those immune cells to destroy tumors. Approved drugs include inhibitors against the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Such drugs have become standard of care in the treatment of many malignancies.
Earlier studies suggested these drugs work better in patients whose tumors have a very large number of mutated proteins, which offer plentiful targets for T cells to attack. However, the new study shows that for at least 50% of patients whose tumors have a high tumor mutational burden (TMB), checkpoint blockade inhibitors don’t work at all.
The MIT team set out to explore why some patients respond better than others, by designing mouse models that closely mimic the progression of tumors with high TMB. The new mouse models carry mutations in genes that drive cancer development in the colon and lung, as well as a mutation that shuts down the DNA mismatch repair system in these tumors.
“We verified that we were very efficiently inactivating the DNA repair pathway, resulting in lots of mutations. The tumors looked just like they look in human cancers, but they were not more infiltrated by T cells, and they were not responding to immunotherapy,” Westcott says.
This lack of response, the team surmised, appears to be the result of intratumoral heterogeneity—while the tumors have many mutations, each cell in the tumor tends to have different mutations than most others. As a result, each individual cancer mutation is “subclonal,” meaning that it is expressed in a minority of cells. (A “clonal” mutation is one that is expressed in all of the cells.)
The researchers then explored what happened as they changed the heterogeneity of lung tumors in mice. In tumors with clonal mutations, checkpoint inhibitors were very effective. However, as the researchers increased the heterogeneity by mixing tumor cells with different mutations, they found that the treatment became less effective.
“You can have these potently immunogenic tumor cells that otherwise should lead to a profound T cell response, but at this low clonal fraction, they completely go stealth, and the immune system fails to recognize them,” Westcott says. “There’s not enough of the antigen that the T cells recognize, so they’re insufficiently primed and don’t acquire the ability to kill tumor cells.”
To see if these findings might extend to human patients, the researchers analyzed data from two small clinical trials of people who had been treated with checkpoint blockade inhibitors for either colorectal or stomach cancer. After analyzing the sequences of the patients’ tumors, they found that patients’ whose tumors were more homogeneous responded better to the treatment.
