Cancer Breakthrough: Mutations in Tumors Can Be Harrowing, So Beware: Immunotherapy Reactions Could Be Predicted

Cancer Breakthrough: Mutations in Tumors Can Be Harrowing, So Beware: Immunotherapy Reactions Could  ...

As a chess match captured in five snapshots, the interaction between immune cells (white) and tumor cells harboring persistent mutations (red) is shown. The piece placement is drawn from a Kasparov vs. Deep Blue game.

With varying degrees of success, cancer researchers have attempted to estimate a patient's response to immunotherapy by using the tumor mutation burden (TMB). These researchers have now discovered that a specific subset of mutations within the TMB, referred to as "persistent mutations," are less likely to be eliminated as cancer progresses, increasing tumors' ability to recognize and respond to immunotherapy.

This repeat mutation load may assist clinicians in more precisely selecting patients for clinical trials of novel immunotherapies or predicting a patient's treatment outcome with immune checkpoint blockade, an immunotherapy technique.

The study was just published in the Nature Medicine journal.

According to senior research author Valsamo Anagnostou, M.D., an associate professor of oncology at Johns Hopkins, the most biochemically relevant subset of mutations in the overall TMB is located in aneuploid regions (regions with additional or missing genetic material).

Cancer cells exploit this capability, shutting down immune responses targeting cancer cells. Checkpoint blockade is a type of immunotherapy that uses a medication or a combination of drugs to break down immune cells so they can work against the cancer.

According to Anagnostou, not all TMB mutations carry the same weight as within the overall TMB, rather than a subset of mutations being more likely to be major drivers of immunologic tumor control in the context of immunotherapy.

Cancer genomes are aneuploid, meaning there may be one copy of some chromosomes or multiple copies of others in cancer cells. Mutations residing in these genomic regions may be predominant as cancer develops and evolves, and in the case of mutations present in multiple copies, it is improbable that all might be removed with a single chromosomal deletion.

"These "stubborn," or persistent, mutations are always present in cancer cells, and these mutations may render the cancer cells perpetually visible to the immune system," says the author. "In the case of immunotherapy, this response is enhanced, and the immune system continues to eliminate cancer cells that harbor these persistent mutations over time."

Anagnostou and his colleagues conducted several investigations in order to arrive at these conclusions.

According to the study's first author, Noushin Niknafs, Ph.D., who works at the Johns Hopkins Kimmel Cancer Center, persistent mutations were found to be up to 53% different among individual tumor types and a median re-classification rate of 33% across tumor types.

The researchers examined genome regions with a single copy and two copies per cell, concluding that mutation losses in single copy regions were less likely than in the entire TMB, where the persistence level differed from the overall TMB.

The authors used data from seven published cohorts of patients who received immune checkpoint blockade treatment across three tumor types, including melanoma, non-small cell lung cancer, and mesothelioma, totaling 485 patients. Again, the researchers observed that overall TMB and persistent mutation burden were different across the cancers analyzed.

Further research examined whether a higher persistent mutation load (pTMB) was linked with improved clinical outcomes among previously untreated tumors from the Cancer Genome Atlas. They found a significant association with prolonged overall survival for lung squamous cell cancer, melanoma, and uterine cancer, although it did not apply to other cancer types.

The researchers hypothesized that tumors with a high pTMB would be most visible to the immune system and would therefore regress after being exposed to immunotherapy. TMB, the number of loss-prone mutations, or tumor aneuploidy, suggested that tumors with a high pTMB would be more optimally distinguished from tumors that did not respond to immunotherapy.

These findings demonstrate the clinical utility of persistent mutations. Future steps include a more extensive validation of the findings as well as prospective analyses to investigate the role of persistent mutation load in cancer immunotherapy.

Weshin Niknafs, Archana Balan, Christopher Cherry, Kim Monkhorst, Xiaoshan M. Shao, Benjamin Levy, Josephine Feliciano, Christine L. Hann, Drew M. Pardoll, Victor E. Velculescu, and Valsamo Anagnostou, 26 January 2023, Nature Medicine. DOI: 10.1038/s41591-022-02163-w

The National Institutes of Health, the BloombergKimmel Institute for Cancer Immunotherapy, the Johns Hopkins University, the Department of Defense's Congressionally Directed Medical Research Program, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center, the V Foundation, and the LUNGevity Foundation all funded the research.

Anagnostou has received research funding from AstraZeneca, Personal Genome Diagnostics, and Bristol Myers Squibb over the previous five years. She is an inventor on six patent applications filed by The Johns Hopkins University and related to cancer genomic studies, ctDNA therapeutic response monitoring, and immunogenomic features of response to immunotherapy that have been licensed to one or more entities.

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