Use of a novel microbiome modulator improves anticancer immunity in a murine model of malignant pleural mesothelioma

Our plain-English summary of Use of a novel microbiome modulator improves anticancer immunity in a murine model of malignant pleural mesothelioma, by C. Gattlen, K.R. Frank, D.N. Marie, et al (JTCVS Open, 2024).

The study

• Authors: C. Gattlen, K.R. Frank, D.N. Marie, A. Trompette, L.E. Chriqui, Y. Hao, E. Abdelnour, M. Gonzalez, T. Krueger, P.J. Dyson, S. Siankevich, C. von Garnier, N.D.J. Ubags, S. Cavin, J.Y. Perentes
• Journal: JTCVS Open
• Published: 2024;18:324-344
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: Malignant pleural mesothelioma is a fatal disease and a clinical challenge, as few effective treatment modalities are available. Previous evidence links the gut microbiome to the host immunoreactivity to tumors. We thus evaluated the impact of a novel microbiome modulator compound (MMC) on the gut microbiota composition, tumor immune microenvironment, and cancer control in a model of malignant pleural mesothelioma.

Methods: Age- and weight-matched immunocompetent (n = 23) or athymic BALB/c mice (n = 15) were randomly assigned to MMC or no treatment (control) groups. MMC (31 ppm) was administered through the drinking water 14 days before AB12 malignant mesothelioma cell inoculation into the pleural cavity. The impact of MMC on tumor growth, animal survival, tumor-infiltrating leucocytes, gut microbiome, and fecal metabolome was evaluated and compared with those of control animals.

Results: The MMC delayed tumor growth and significantly prolonged the survival of immunocompetent animals (P = .0015) but not that of athymic mice. The improved tumor control in immunocompetent mice correlated with increased infiltration of CD3+CD8+GRZB+ cytotoxic T lymphocytes in tumors. Gut microbiota analyses indicated an enrichment in producers of short chain fatty acids in MMC-treated animals. Finally, we observed a positive correlation between the level of fecal short chain fatty acids and abundance of tumor-infiltrating cytotoxic T cells in malignant pleural mesothelioma.

Conclusions: MMC administration boosts antitumor immunity, which correlates with a change in gut microbiome and metabolome. MMC may represent a valuable treatment option to combine with immunotherapy in patients with cancer.

© 2024 The Author(s).

In plain English

This animal experiment used a mouse model of malignant pleural mesothelioma, which the authors describe as strongly associated with exposure to asbestos or asbestos-like fibres; the AB12 tumour cells came from asbestos-exposed BALB/c mice. Thirty immunocompetent and 20 athymic BALB/c mice were randomly assigned to no treatment or a prebiotic, MMC (31 ppm in drinking water), from 14 days before AB12-luc cells were injected into the left pleural cavity. After excluding mice without tumour engraftment or with abdominal masses, 23 and 15 remained. In immunocompetent mice, MMC slowed tumour growth and lengthened survival, counted from when tumours reached a set bioluminescence level (median 10 versus 7 days; hazard ratio 0.3532, 95% CI 0.1365-0.9140). In athymic mice the survival difference was not statistically significant (hazard ratio 0.8691, 95% CI 0.3129-2.4140). Tumours of MMC-treated immunocompetent mice held more CD8 and granzyme B-positive T cells and macrophages; gut bacteria differed in colon and ileum. Faecal short-chain fatty acid levels did not differ between groups. In MMC-treated mice, 2-methylbutyric, isobutyric and isovaleric acid correlated positively with tumour granzyme B-positive CD8 T cells, and butyric acid with CD8 T cells.

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: animal experiment (randomised, controlled preclinical study in mice)
• Who was studied: 10- to 12-week-old BALB/c mice in Lausanne, Switzerland: 30 immunocompetent (15 untreated, 15 MMC) and 20 athymic (10 untreated, 10 MMC) were allocated. Seven immunocompetent and 5 athymic mice were excluded for no tumour engraftment or an abdominal mass, leaving 23 immunocompetent (11 untreated, 12 MMC) and 15 athymic (7 untreated, 8 MMC) for the tumour growth and survival analyses.
• Exposure: A prebiotic microbiome modulator composition (EMB008, MMC) derived from Saccharomyces cerevisiae yeast, given at 31 ppm in drinking water (estimated 6.2 mg/kg body weight per day). It was started 14 days before tumour cell inoculation and continued throughout the study.
• Main results:
  • In immunocompetent mice, MMC prolonged survival (median 10 days versus 7 days untreated), with a hazard ratio of 0.3532 (95% CI, 0.1365-0.9140). In athymic mice the hazard ratio was 0.8691 (95% CI, 0.3129-2.4140). Survival time was counted from when tumours reached a set bioluminescence level marking the start of exponential tumour growth, not from tumour cell injection.
  • The survival curves started at the bioluminescence level associated with the beginning of exponential tumour growth.
  • In athymic (T-cell-deficient) mice, the authors reported no impact of MMC on tumour growth or survival; the survival difference was not statistically significant (P = .6980).
  • Tumours of MMC-treated immunocompetent mice had more CD3+CD8+ T cells (P = .0174), while CD3+CD4+ T cells were unchanged (P = .1949).
  • In MMC-treated mice, a higher proportion of tumour CD8 T cells expressed granzyme B (P = .0013). CD8 cells expressing CTLA-4 (P = .0081) and PD-1 (P = .0649) were also increased.
  • Total macrophage infiltration rose with MMC (P = .0080), but the M1/M2 ratio was unchanged (P = .2812).
  • Gut microbial community composition differed in the colon (P = .0012) and ileum (P = .0170) of MMC-treated mice. Alistipes, the Rikenellaceae RC9 gut group and Muribaculaceae were enriched, and Mucispirillum and Lachnospiraceae were reduced.
  • Faecal short-chain fatty acid levels did not differ between the MMC and control groups.
  • In MMC-treated mice, tumour CD8+GRZB+ T cells correlated positively with faecal 2-methylbutyric acid (R2 = 0.97), isobutyric acid (R2 = 0.91) and isovaleric acid (R2 = 0.88). Butyric acid correlated with tumour CD8+ T cells (R2 = 0.91).
  • Across animals, tumour CD8+GRZB+ T cells correlated positively with survival (Spearman 0.5965, P = .0164), whereas CD8 or CD4 infiltration alone did not.
• The authors' conclusion: The authors concluded that MMC administration boosted antitumour immunity in this model, correlating with changes in the gut microbiome and metabolome. They suggested it may be worth testing in combination with immune checkpoint inhibition in patients with solid tumours.
• Limitations the authors state:
  • Only one mesothelioma mouse model (the biphasic AB12 model) was tested.
  • Immune cell infiltration was measured only by immunostaining of tumour sections, without characterisation by flow cytometry.
  • MMC was given in drinking water, with the dose estimated from average water consumption. It was also given preventively, before tumour inoculation, rather than as a treatment.
  • The small sample size and the limits of 16S rRNA sequencing prevented linking specific bacterial species to immune cell infiltration or survival.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Pleural Cavity, Immunotherapy.

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