Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types

Our plain-English summary of Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types, by T. van den Ende, H.G. van den Boorn, N.M. Hoonhout, et al (Biochimica et Biophysica Acta. Reviews on Cancer, 2020).

The study

• Authors: T. van den Ende, H.G. van den Boorn, N.M. Hoonhout, F.S. van Etten-Jamaludin, S.L. Meijer, S. Derks, T.D. de Gruijl, M.F. Bijlsma, M.G.H. van Oijen, H.W.M. van Laarhoven
• Journal: Biochimica et Biophysica Acta. Reviews on Cancer
• Published: 2020;1874(1):188386
• Type of article: Systematic review
• Cited by: 91 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect of these modalities on the TIME could aid in the development of improved treatment strategies. Our aim was to systematically review studies investigating the influence of CT, RT or CRT on different TIME markers.

Methods: The EMBASE (Ovid) and PubMed databases were searched until January 2019 for prospective or retrospective studies investigating the dynamics of the local TIME in cancer patients (pts) treated with CT, RT or CRT, with or without targeted agents. Studies could either compare baseline and follow-up specimens - before and after treatment - or a treated versus an untreated cohort. Studies were included if they used immunohistochemistry and/or flow cytometry to assess the TIME.

Results: In total we included 110 studies (n = 8850 pts), of which n = 89 (n = 6295 pts) compared pre-treatment to post-treatment specimens and n = 25 (n = 2555 pts) a treated versus an untreated cohort (4 studies conducted both comparisons). For several tumor types (among others; breast, cervical, esophageal, ovarian, rectal, lung mesothelioma and pancreatic cancer) remodeling of the TIME was observed, leading to a potentially more immunologically active microenvironment, including one or more of the following: an increase in CD3 or CD8 lymphocytes, a decrease in FOXP3 Tregs and increased PD-L1 expression. Both CT and CRT were able to immunologically alter the TIME.

Conclusion: The TIME of several tumor types is significantly altered after conventional therapy creating opportunities for concurrent or sequential immunotherapy.

Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

In plain English

This was a systematic review. The authors searched the EMBASE and PubMed databases for studies published before 29 January 2019 that examined immune cells and immune markers inside the tumors of cancer patients. The studies compared tumor samples taken before and after chemotherapy, radiotherapy or chemoradiotherapy, or compared treated with untreated patients. The authors included 110 articles covering 8850 patients across many cancer types. The article does not study asbestos exposure; its only mesothelioma data come from one included study of pleural mesothelioma. Among studies comparing samples before and after treatment, 35 of 44 reported more CD8 T-cells (18 of them statistically significant). Of 26 such studies, 18 reported fewer FOXP3 regulatory T-cells (8 significant). Of 41, 25 reported higher PD-L1 (12 significant). In the pleural mesothelioma study, 15 patients given platinum/pemetrexed chemotherapy before surgery showed significant increases in CD3, CD8 and PD-L1. Some cancers, including oral cavity and cervical carcinoma, showed decreases. The authors concluded that results diverged by tumor type, treatment and method of analysis. They said combinations with immunotherapy should be evaluated for specific tumor types and treatment backbones.

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: Systematic review of published prospective or retrospective studies (performed in line with PRISMA guidelines)
• Who was studied: 110 published articles with 8850 cancer patients across many tumor types, identified in EMBASE (Ovid) and PubMed searches of literature published before 29 January 2019; 89 articles (6295 patients) compared before/after samples and 25 (2555 patients) compared treated vs untreated cohorts, with 4 doing both
• Exposure: Cancer treatment: chemotherapy, radiotherapy or chemoradiotherapy, with or without targeted agents. No asbestos exposure was studied.
• Main results:
  • Of 44 studies comparing tumor samples before and after treatment, 35 reported an increase in CD8 staining, of which 18 were statistically significant; 21 of the 44 reported a statistically significant difference.
  • Of 26 studies comparing before/after specimens, 18 observed a decrease in FOXP3+ regulatory T-cells after treatment, 8 of them statistically significant.
  • Of 41 studies comparing before/after specimens, 25 reported an increase in PD-L1 expression, 12 of them significant.
  • Across all studies, the sample size weighted median difference was an increase of 24.6% in CD8 and a 25.2% decrease in FOXP3+ cells.
  • Across all studies, the sample size weighted median difference in PD-L1 expression was an increase of 56.6%.
  • In one included study of pleural mesothelioma (Pasello et al. 2018, 15 patients, stage I to IV, platinum plus pemetrexed chemotherapy before surgery), CD3, CD8 and PD-L1 increased with statistical significance, and CD4, CD68 and CD20 increased without a significance mark.
  • Other tumor types showed decreases after therapy, including oral cavity, nasopharyngeal, esophageal squamous cell and cervical carcinoma.
• The authors' conclusion: The authors concluded that, although several tumor types showed a more immunogenic microenvironment after treatment, results diverged by tumor type, treatment modality and method of analysis. They said combinations with immunotherapy should therefore be evaluated for specific tumor types and chemo/radiotherapy backbones.
• Limitations the authors state:
  • Comparisons across studies were hampered by differences in the laboratory methods each study used.
  • Targeted agent monotherapy and other local therapies were not included.
  • The authors could not separate the effects of individual treatment regimens.

Topics

Medical terms in this study, explained in our Lexicon: Systematic Review, Chemotherapy, Immunohistochemistry, Mesothelioma, PD-L1, Immunotherapy.

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