OncoImmunology (Dec 2023)

Eribulin mesylate exerts antitumor effects via CD103

  • Kazumasa Oya,
  • Yoshiyuki Nakamura,
  • Rei Watanabe,
  • Ryota Tanaka,
  • Yuki Ichimura,
  • Noriko Kubota,
  • Yutaka Matsumura,
  • Hideaki Tahara,
  • Naoko Okiyama,
  • Manabu Fujimoto,
  • Toshifumi Nomura,
  • Yasuhiro Fujisawa

DOI
https://doi.org/10.1080/2162402X.2023.2218782
Journal volume & issue
Vol. 12, no. 1

Abstract

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ABSTRACTEribulin mesylate (ERB) is a synthetic analog of halichondrin B, inhibiting tumor cell growth by disrupting microtubule function. Recently, anticancer drugs have been shown to not only act directly on tumor cells but also to exert antitumor effects by modifying the tumor environment. Although ERB has also been speculated to modify the tumor microenvironment including the immune response to tumors, the precise mechanism remains unclear. In our study, ERB suppressed the tumor growth of MC38 colon cancer in wildtype mice, whereas ERB failed to inhibit the tumor growth in Rag1-deficient mice which lack both B and T cells. Moreover, depletion of either CD4+ or CD8+ T cells abrogated the antitumor effect of ERB, indicating that both CD4+ and CD8+ T cells play an important role in ERB-induced antitumor effects. Furthermore, ERB treatment increased the number of tumor infiltrating lymphocytes (TILs) as well as the expression of activation markers (CD38 and CD69), immune checkpoint molecules (LAG3, TIGIT and Tim3) and cytotoxic molecules (granzyme B and perforin) in TILs. ERB upregulated E-cadherin expression in MC38. CD103 is a ligand of E-cadherin and induces T-cell activation. ERB increased the proportion of CD103+ cells in both CD4+ and CD8+ TILs. The ERB-induced antitumor effect with the increased TIL number and the increased expression of activation markers, inhibitory checkpoint molecules and cytotoxic molecules in TILs was abrogated in CD103-deficient mice. Collectively, these results suggest that ERB exerts antitumor effects by upregulation of E-cadherin expression in tumor cells and subsequent activation of CD103+ TILs.

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