S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor

Our plain-English summary of S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor, by N.T. Nguyen, A. Mitsuhashi, H. Ogino, et al (Cancer Science, 2023).

The study

• Authors: N.T. Nguyen, A. Mitsuhashi, H. Ogino, H. Kozai, H. Yoneda, T. Afroj, S. Sato, H. Nokihara, T. Shinohara, Y. Nishioka
• Journal: Cancer Science
• Published: 2023;114(2):384-398
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.

© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory study in mice and cultured cells at Tokushima University, Japan. It did not study asbestos exposure. The authors grew tumors in mice from a mouse mesothelioma cell line (AB1-HA) or a mouse lung cancer cell line (3LL). They treated the mice with chemotherapy drugs approved for chest cancers, including pemetrexed, 5-FU and S-1, an oral drug containing a precursor of 5-FU. They measured tumor growth and myeloid-derived suppressor cells (MDSCs), immune cells that can weaken the body's attack on tumors. Of the drugs tested, only 5-FU and S-1 suppressed tumor growth and MDSC build-up in spleen and tumor. S-1, but not pemetrexed, increased T cells and dendritic cells in tumors and lowered tumor Bv8 and S100A8. In mice with mesothelioma tumors, S-1 plus an anti-PD-1 immunotherapy antibody suppressed tumors more than either treatment alone. Carboplatin plus S-1 plus anti-PD-1 outperformed carboplatin plus pemetrexed plus anti-PD-1. The authors concluded that S-1 depletes MDSCs by lowering tumor Bv8 and S100A8. They noted that the results come only from preclinical models.

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 (mouse tumor models) with in vitro cell-culture experiments
• Who was studied: Male BALB/c mice injected with the mouse mesothelioma cell line AB1-HA, and male C57BL/6 mice injected with the mouse lung cancer cell line 3LL, at Tokushima University, Japan. Group sizes in the figures range from n = 3 to n = 10 per group. No dates of the experiments are given.
• Exposure: Chemotherapy drugs, not asbestos. Single intraperitoneal doses on day 14 of pemetrexed (100 mg/kg), 5-FU (80 mg/kg), carboplatin, cisplatin, vinorelbine, paclitaxel, docetaxel or gemcitabine, or oral S-1 at 8.3 mg/kg/day from day 14 to day 20. Some mice also received anti-PD-1 antibody (100 μg/mouse/day twice a week), alone or in combinations.
• Main results:
  • In AB1-HA mesothelioma-bearing mice, only 5-FU and S-1 suppressed tumor growth and MDSC accumulation in both spleen and tumor. Pemetrexed and paclitaxel did not. Results are shown in figures, not as numbers in the text.
  • In tumor tissue, S-1 increased CD4+ T cells, CD8+ T cells and dendritic cells; pemetrexed did not (n = 5 per group).
  • In cell culture, 5-FU was directly toxic to the tumor cells but had no significant effect on the survival of MDSCs.
  • 5-FU in cell culture and S-1 in mice lowered gene expression of S100A8, Bv8 and iNOS. Pemetrexed did not.
  • Silencing S100A8 in AB1-HA tumor cells suppressed tumor development and MDSC infiltration in mice; silencing Bv8 also delayed tumor progression and decreased MDSCs.
  • In AB1-HA mesothelioma-bearing mice, S-1 combined with anti-PD-1 antibody suppressed tumors more than either treatment alone.
  • Carboplatin plus S-1 plus anti-PD-1 antibody had greater antitumor effects than carboplatin plus pemetrexed plus anti-PD-1 blockade (n = 6 per group).
• The authors' conclusion: The authors concluded that S-1 depletes tumor-infiltrating MDSCs by downregulating tumor-derived Bv8 and S100A8, and that S-1-containing regimens improved the efficacy of immune checkpoint inhibitors in a preclinical model.
• Limitations the authors state:
  • The findings come only from preclinical models; the authors state that clinical studies are needed.
  • The authors state that the way these drugs lower Bv8 and S100A8 in tumor cells was not sufficiently explained.

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: checkpoint inhibitors, Lung Cancer, Pleural Mesothelioma, Fluorouracil (5-FU), Pemetrexed (Alimta), Carboplatin, Tumor Microenvironment.

Related studies

• Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells — H. Yoneda, A. Mitsuhashi, et al. (2024)
• Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies — H. Kozai, H. Ogino, et al. (2024)
• Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC — F. Facchinetti, A. Marabelle, et al. (2016)
• COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function — J.D. Veltman, M.E. Lambers, et al. (2010)
• Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers — L. Kara-Terki, L. Treps, et al. (2020)
• Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma — D. Horio, T. Minami, et al. (2020)

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