Eribulin mesylate exerts antitumor effects via CD103

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Eribulin mesylate (ERB), a synthetic analog of halichondrin B, inhibits tumor cell growth via microtubule disruption.
• Anticancer drugs can modulate the tumor microenvironment, including immune responses, but ERB's precise mechanism is unclear.

Purpose of the Study:

• To elucidate the mechanism by which ERB affects the tumor microenvironment and immune response.
• To investigate the role of T cells and E-cadherin in ERB's antitumor effects.

Main Methods:

• Tumor growth inhibition was assessed in wildtype, Rag1-deficient, and CD103-deficient mice treated with ERB.
• T cell depletion (CD4+ or CD8+) was performed to evaluate their role in ERB's efficacy.
• Flow cytometry was used to analyze immune cell populations, activation markers, immune checkpoint molecules, and cytotoxic molecules in tumor-infiltrating lymphocytes (TILs).
• E-cadherin and CD103 expression in tumor cells and TILs were quantified.

Main Results:

• ERB suppressed MC38 colon cancer growth in wildtype mice but not in T cell-deficient Rag1 mice.
• Depletion of CD4+ or CD8+ T cells abrogated ERB's antitumor effect, highlighting the critical role of T cells.
• ERB increased TILs, upregulated activation (CD38, CD69), immune checkpoint (LAG3, TIGIT, Tim3), and cytotoxic (granzyme B, perforin) markers in TILs.
• ERB upregulated E-cadherin in tumor cells and increased CD103 expression on CD4+ and CD8+ TILs.
• The antitumor effect of ERB was abolished in CD103-deficient mice.

Conclusions:

• ERB exerts antitumor effects by activating CD103+ T cells, dependent on E-cadherin expression in tumor cells.
• ERB modulates the tumor microenvironment, enhancing T cell-mediated anti-tumor immunity.