Coupling of response biomarkers between tumor and peripheral blood in patients undergoing chemoimmunotherapy

Our plain-English summary of Coupling of response biomarkers between tumor and peripheral blood in patients undergoing chemoimmunotherapy, by W.L. Chin, A.M. Cook, J. Chee, et al (Cell Reports. Medicine, 2025).

The study

• Authors: W.L. Chin, A.M. Cook, J. Chee, N. Principe, T.S. Hoang, J. Kidman, K.P.W. Hmon, Y. Yeow, M.E. Jones, R. Hou, E. Denisenko, A.M. McDonnell, C.C. Hon, J. Moody, D. Anderson, S. Yip, M.M. Cummins, M.R. Stockler, P.S. Kok, C. Brown, T. John, S.C. Kao, D.J. Karikios, K.J. O'Byrne, B.G.M. Hughes, R.A. Lake, A.R.R. Forrest, A.K. Nowak, T. Lassmann, W.J. Lesterhuis
• Journal: Cell Reports. Medicine
• Published: 2025;6(1):101882
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers to guide treatment decisions. Here, we combine time course RNA sequencing (RNA-seq) of peripheral blood mononuclear cells with pre-treatment tumor transcriptome data from the single-arm, phase 2 DREAM trial (N = 54). Single-cell RNA-seq and T cell receptor sequencing (TCR-seq) reveal that CD8+ T effector memory (TEM) cells with stem-like properties are more abundant in peripheral blood of responders and that this population expands upon treatment. These peripheral blood changes are linked to the transcriptional state of the tumor microenvironment. Combining information from both compartments, rather than individually, is most predictive of response. Our study highlights complex interactions between the tumor and immune cells in peripheral blood during objective tumor responses to chemoimmunotherapy. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616001170415.

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

In plain English

This study analyzed blood and tumor samples from the DREAM trial, a single-arm phase 2 trial of 54 people with previously untreated, unresectable pleural mesothelioma in Australia. They received the immunotherapy drug durvalumab plus pemetrexed and platinum chemotherapy. Asbestos exposure was not studied. People who achieved progression-free survival at 6 months, meaning alive without tumor progression, were counted as responders (31). The other 23 were non-responders. The authors measured gene activity in blood taken before treatment and before cycles two and three, and in stored tumor biopsies. CD8+ T effector memory cells, a type of immune cell, were more abundant in responders' blood, and a 'stem-like' subgroup persisted over time in responders. Patients with stronger stem-like signals in blood had significantly longer progression-free and overall survival. Combining tumor data with the first two blood samples best separated responders from non-responders. The authors concluded that combining blood and tumor analyses has potential for predicting response. They noted three limits. A randomized comparison is needed to separate chemotherapy's effect from the combination's. Steroid premedication may have affected later blood samples. Larger studies are needed.

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: Biomarker (gene expression) analysis of blood and archival tumor samples from a single-arm, multi-center phase 2 clinical trial (DREAM), with no randomized comparison group
• Who was studied: 54 participants with previously untreated, unresectable pleural mesothelioma, enrolled at 8 Australian sites between December 28, 2016 and September 27, 2017. Bulk blood RNA sequencing was done for 40 participants, single-cell blood sequencing for 35, and tumor gene profiling for 46. The combined tumor-plus-blood analysis included 34 participants (18 responders, 16 non-responders).
• Exposure: Treatment, not asbestos. Participants received the anti-PD-L1 antibody durvalumab every 3 weeks with pemetrexed and cisplatin (the methods say cisplatin or carboplatin) for up to 6 cycles, followed by maintenance durvalumab. The article does not report participants' asbestos exposure.
• Main results:
  • Responders were defined as those achieving progression-free survival at 6 months after starting treatment (the trial's primary endpoint). Of the 54 participants, 31 were responders and 23 were non-responders.
  • In bulk blood gene data (40 participants), no individual genes differed between responders and non-responders. The only gene set enriched in responders was CD8-positive alpha beta T cell differentiation, at time points 1 and 2.
  • In single-cell blood data (390,373 cells from 35 participants), CD8+ T effector memory (TEM) cells were the only cell type more abundant in responders across time points
  • Proportions of expanded CD8+ TEM clones were significantly higher in responders
  • Responders had more clones of a stem-like, progenitor-exhausted CD8+ TEM subcluster (cluster 2) that were present at all time points. This was not seen for clusters 1 and 3.
  • Participants with higher enrichment of the stem-like T cell signature in blood had significantly longer progression-free survival and overall survival. The text gives no survival figures.
  • Among 34 participants, a model combining tumor data with blood from the first two time points best separated responders from non-responders, with a balanced error rate of 0.24
  • The predictive genes did not apply to every participant: 7 responders showed some but not all of the identified immune features
• The authors' conclusion: The authors concluded that their study demonstrates the potential utility of combining blood and tumor tissue analyses to predict response to chemoimmunotherapy in mesothelioma patients
• Limitations the authors state:
  • Without a randomized comparison, the response to chemotherapy could not be separated from the response to the immunotherapy-chemotherapy combination
  • The second and third blood samples were taken after dexamethasone premedication, which may have lowered lymphocyte numbers at the later time points
  • The sample size did not allow a definitive analysis of specific subsets within the CD8+ TEM population
  • Larger, randomized studies are needed to validate and extend the findings

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Chemotherapy, PD-L1, Mesothelioma, STEM, Tumor Microenvironment, Clinical Trial.

Related studies

• Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma--a pilot study — D.G. Weber, G. Johnen, et al. (2012)
• Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects — S. Guarrera, C. Viberti, et al. (2019)
• Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report — N. Beije, J. Kraan, et al. (2017)
• Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types — T. van den Ende, H.G. van den Boorn, et al. (2020)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)
• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in — A.K. Nowak, W.J. Lesterhuis, et al. (2020)

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