Persistent mutation burden drives sustained anti-tumor immune responses

Our plain-English summary of Persistent mutation burden drives sustained anti-tumor immune responses, by N. Niknafs, A. Balan, C. Cherry, et al (Nature Medicine, 2023).

The study

• Authors: N. Niknafs, A. Balan, C. Cherry, K. Hummelink, K. Monkhorst, X.M. Shao, Z. Belcaid, K.A. Marrone, J. Murray, K.N. Smith, B. Levy, J. Feliciano, C.L. Hann, V. Lam, D.M. Pardoll, R. Karchin, T.Y. Seiwert, J.R. Brahmer, P.M. Forde, V.E. Velculescu, V. Anagnostou
• Journal: Nature Medicine
• Published: 2023;29(2):440-449
• Cited by: 130 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

© 2023. The Author(s).

In plain English

This genetic study of tumors did not look at asbestos or any other exposure. The authors analyzed DNA from 9,242 tumors across 31 tumor types in The Cancer Genome Atlas. They also analyzed 524 immunotherapy-treated patients with melanoma, non-small-cell lung cancer, mesothelioma or head and neck cancer. They counted 'persistent' mutations: those in single-copy parts of the genome or present in multiple copies per cell. Mesotheliomas were among tumor types with more single-copy genome, and for them only single-copy mutations were counted. Among 40 mesothelioma patients given durvalumab plus platinum-pemetrexed chemotherapy, the persistent mutation count was linked to response (P = 0.03), while the association for overall mutation burden was not statistically significant (P = 0.12). In the other cohorts, persistent mutation counts separated responders from nonresponders better than overall mutation burden, which was also significantly linked to response in the melanoma and both lung cancer cohorts. In eight lung cancer patients biopsied before and after treatment, 358 of 363 lost clonal mutations were 'loss-prone'. The authors concluded that persistent mutations may drive sustained immune tumor control.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective genomic analysis of public tumor data (The Cancer Genome Atlas, TCGA) and published immunotherapy cohorts, plus a new head and neck cancer cohort, serial tumor biopsies, and a laboratory T cell assay
• Who was studied: 9,242 TCGA tumors across 31 tumor types (including mesothelioma), plus 524 patients treated with immune checkpoint blockade: melanoma (n = 202), two non-small-cell lung cancer cohorts (n = 74 and n = 169), mesothelioma (n = 40; 16 nonresponders, 24 responders) and HPV-negative head and neck squamous cell carcinoma (n = 39, treated at the University of Chicago)
• Exposure: No asbestos or fiber exposure was studied. The 'exposure' was immune checkpoint blockade therapy; the mesothelioma cohort received durvalumab plus platinum-pemetrexed chemotherapy. The features examined were tumor mutation counts (persistent, loss-prone and total).
• Main results:
  • Across TCGA tumors, the rate of genomic loss was consistently lower in single-copy (haploid) regions than in two-copy regions.
  • Mesotheliomas (MESO) were among the tumor types with a higher fraction of the genome in the single-copy state, along with cholangiocarcinomas, pancreatic adenocarcinomas and kidney chromophobe tumors.
  • For mesotheliomas, the persistent mutation burden counted only mutations in single-copy regions of the genome.
  • In the mesothelioma cohort (n = 40), Mann–Whitney P values for distinguishing responders from nonresponders were: pTMB 0.03, clonal pTMB 0.05, loss-prone mutations 0.09, TMB 0.12. The figure legend describes the TMB result as non-significant. Effect sizes in this cohort were pTMB d = −0.74, TMB d = −0.51 and loss-prone d = −0.58.
  • In the melanoma cohort (n = 202), pTMB distinguished responders from nonresponders with P = 2.3 × 10^−6, compared with P = 2.6 × 10^−5 for TMB. The authors reported that pTMB outperformed TMB in all immunotherapy cohorts.
  • In the non-small-cell lung cancer cohorts, both pTMB and TMB differed between responders and nonresponders. In NSCLC-Anagnostou (n = 74), pTMB P = 1.3 × 10^−4 and TMB P = 4.3 × 10^−4. In NSCLC-Shim (n = 169), pTMB P = 1.9 × 10^−3 and TMB P = 8.0 × 10^−3.
  • Tumor aneuploidy and whole-genome doubling alone failed to predict immunotherapy response in all cohorts. For mesothelioma, the aneuploidy P was 0.07 and the whole-genome doubling P was 0.23.
  • In serial biopsies from eight non-small-cell lung cancer patients, 363 of 2,836 clonal baseline mutations were lost after immunotherapy. Of these, 358 (98.6%) were loss-prone mutations.
  • In untreated TCGA tumors, an association between pTMB and longer overall survival was reported only for lung squamous cell carcinoma, melanoma and uterine carcinosarcoma, and not for any other cancer type studied.
  • In immunotherapy-treated melanomas, tumors with high pTMB showed enrichment of interferon-gamma and inflammatory gene sets.
• The authors' conclusion: The authors concluded that mutations in single-copy regions or present in multiple copies are unlikely to be lost under immunotherapy, and may serve as a key driver of sustained immunologic tumor control.
• Limitations the authors state:
  • Microsatellite instability status was not uniformly documented in the immunotherapy cohorts. The authors considered it an unlikely confounder because of its low prevalence.
  • Sample size for comparing tumors classified differently by pTMB and TMB was sufficient only in the combined melanoma cohort.
  • Reported P values were not adjusted for multiple hypothesis testing unless explicitly stated.
  • The authors noted limitations of neoantigen-predicting algorithms in identifying biologically relevant neoepitopes.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Lung Cancer, Mesothelioma, Tumor Microenvironment.

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