Tumor microenvironment
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Tumor mutation burden (TMB) has become a biomarker used to predict patient response to specific immunotherapies. Now, new evidence from researchers at the Johns Hopkins Kimmel Cancer Center have found that a subset of mutations within the TMB—defined at “persistent mutations”—are less likely than others to be edited out, making them always visible to the immune system, which results in them being more likely to respond to immunotherapies.

Identifying these persistent mutations hold the promise of having a more precise biomarker that will allow clinicians to stratify appropriate patients for enrollment in clinical trials and also predict patient response to receiving a type of immunotherapy called immune checkpoint blockade. Immune checkpoints are the immune system’s signals that either turn on the immune system when it is needed and then turn off again when it has eliminated the threat.

“There’s a lot of frustration in trying to use tumor mutation burden as a universal predictive biomarker of immunotherapy response across cancers,” said Valsamo Anagnostou, MD, PhD, an associate professor of oncology at Johns Hopkins, a senior author of the study published in Nature Medicine. “Therefore, it’s imperative to identify the most biologically meaningful subset of mutations within the overall TMB. Our study showed that such mutations reside in aneuploid regions (regions with extra or missing genetic material) of the genome.”

Cancer cells manipulate human immune response by shutting down the immune system’s response to their presence. Checkpoint blockade drugs are a form of immunotherapy that have been developed to reignite the immune system’s response to cancerous cells.

In addition, cancer cells are known to be aneuploid resulting in one copy of some chromosome or multiple copies of others in cancer cells. The Hopkins team pursued their latest research under the hypothesis that mutations residing in these genomic regions may be retained as cancer evolves. Anagnostou said that in genomic regions with one copy, eliminating that copy would kill that cancer cell. But in cases with multiple copies, it was unlikely that they could all be removed by a single chromosomal deletion.

She noted that these persistent mutations, which are always present in cancer cells, may make cancer cells continuously visible to the immune system. “If the cancer cell is seen by the immune system as something foreign, then there is an anti-tumor immune response,” Anagnostou said. “In the case of immunotherapy, this response is augmented, and the immune system continues to eliminate cancer cells harboring these persistent mutations over time.”

As part of their research, the investigators performed an analysis on 9,000 tumors encompassing 31 tumor types held in the Cancer Genome Atlas. “In looking at how different persistent mutation is compared to the overall TMB, we found re-classification rates of TMB-high/low to persistent mutation load-high/low tumors up to 53% in individual tumor types, and a median re-classification rate of 33% across tumor types,” said Noushin Niknafs, PhD, a research associate at the Johns Hopkins Kimmel Cancer Center.

Examining regions in the genome with a single copy per cell and two copies per cell, the investigators noted that the rate or mutation losses were lower in the regions with a single copy, supporting their hypothesis that mutations in single copy regions would be more difficult to eliminate. The distribution of persistent mutations also differed compared to the overall TMB, where a tumor’s TMB was not always concordant with its persistent mutation load.

In further analyses based on tumors from the Cancer Genome Atlas, the scientists evaluated whether a higher persistent mutation load (pTMB) was linked with clinical outcomes among patients with previously untreated tumors. They found a significant association with prolonged overall survival for lung squamous cell cancer, melanoma and uterine cancer but not for other cancer types studied.

The team then sought to discover whether tumors with high pTMB would be susceptible to treatment with immunotherapies. Evaluating the potential of pTMB, multicopy and single-copy mutations to predict response to immune checkpoint blockade among 542 patients with melanoma, non-small cell lung caner, mesothelioma, and head and neck cancer, the team found that tumors exhibiting high pTMB showed higher rates of therapeutic response, while TMB alone was a less optimal measure of treatment response.

In total, the findings of the Hopkins team supported the clinical utility of pTMB, and the research suggest the need for large-scale validation of the new findings and prospective analysis to further evaluate the role of pTMB to select patients for immunotherapy.

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