MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma

Our plain-English summary of MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma, by S.F. Magkouta, P.C. Vaitsi, M.P. Iliopoulou, et al (Cancers, 2023).

The study

• Authors: S.F. Magkouta, P.C. Vaitsi, M.P. Iliopoulou, A.G. Pappas, C.N. Kosti, K. Psarra, I.T. Kalomenidis
• Journal: Cancers
• Published: 2023;15(20)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens.

Methods: Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players.

Results: Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy.

Conclusions: Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.

In plain English

This was a laboratory study in mice. It did not involve asbestos exposure or human patients. The authors injected two mouse mesothelioma cell lines, AE17 and AB1, into the chest cavity of mice. They then treated the mice with karonudib, an experimental drug that blocks an enzyme called MTH1, either alone or together with an anti-PD-L1 antibody, a type of immunotherapy. Groups held 5 to 8 mice. Macrophages (a kind of immune cell) taken from tumors and from the fluid around the lungs had higher MTH1 levels than macrophages from mice without tumors. Karonudib did not change the number of macrophages in tumors, but it shifted them toward the M1 type. It also significantly increased the expansion of CD8 T cells in tumors, although CD8 T cell entry into tumors rose significantly only in AB1 tumors. The combination slowed tumor growth more than either treatment alone. In the AE17 model it also limited fluid build-up more than either treatment alone. The authors concluded that combined MTH1 and PD-L1 inhibition is a strategy against mesothelioma progression that supports testing in clinical trials.

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 (two syngeneic mouse mesothelioma models) with supporting laboratory cell experiments
• Who was studied: C57BL/6 mice injected in the pleural space with AE17 mouse mesothelioma cells, and Balb/c mice injected with AB1 mouse mesothelioma cells; 8 mice per group (AE17) and 5 mice per group (AB1) in the karonudib-versus-vehicle experiments, and 5 to 8 mice per group in the four-group combination experiments; Athens, Greece
• Exposure: No asbestos exposure was studied. Mice received the MTH1 inhibitor karonudib (90 mg/kg body weight, by mouth), an anti-PD-L1 antibody (200 µg per dose, injected into the abdomen every 3 days), both drugs together, or control treatments.
• Main results:
  • MTH1 levels were significantly higher in macrophages from mesothelioma tumors and from pleural fluid than in macrophages from mice without tumors
  • In karonudib-treated mice, the number of tumor macrophages did not change, but the macrophages showed enhanced M1 polarization
  • In laboratory experiments, extracellular DNA from karonudib-exposed mesothelioma cells activated the NFkB pathway in M2 macrophages
  • Karonudib significantly increased CD8 T cell expansion in tumors. CD8 T cell entry into tumors was only moderately increased, and was significant only in AB1 tumors.
  • Karonudib plus anti-PD-L1 slowed tumor progression more than either single treatment
  • In AE17 tumor-bearing mice, the combination limited pleural fluid build-up more than either single treatment. In AB1 mice, karonudib alone almost abolished fluid formation (less than 50 µL), so no added effect of the combination was seen.
  • In tumors, the combination significantly reduced suppressive T-regulatory cells compared with single treatments
  • The combination produced significant M1 polarization of tumor macrophages in both mouse models
• The authors' conclusion: The authors concluded that their results suggest that dual inhibition of MTH1 and PD-L1 is a strategy against mesothelioma progression, and that they support testing it in clinical trials.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Immunotherapy, Mesothelioma, Oxidative Stress, Tumor Microenvironment, Macrophage, Pleural Effusion.

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