Macrophage-like Blood Cells Are Involved in Inter-Tissue Communication to Activate JAK/STAT Signaling, Inducing Antitumor Turandot Proteins in Drosophila Fat Body via the TNF-JNK Pathway

<b></b> Turandot (Tot) family proteins, which are induced via the JAK/STAT pathway after infection, also suppress lymph gland tumors in <i>Drosophila mxc^mbn1</i> mutant larvae. We investigated the potential role of hemocytes in <i>Tot</i> induction in tumor-bearing mutants via immunostaining and RNAi experiments. Normal hemocytes transplanted into mutant larvae were recruited to the tumor and fat body (FB), suggesting that these cells transmit tumor-related information. The transplanted hemocytes ectopically expressed Unpaired3 (Upd3), which is necessary for the activation of JAK/STAT. Eiger, a <i>Drosophila</i> tumor necrosis factor (TNF) ortholog, was highly expressed in tumors. Depletion of the Eiger receptor in hemocytes reduced <i>Tot</i> levels and eventually enhanced tumor growth. The c-Jun N-terminal kinase (JNK) pathway, acting downstream of the receptor, was also activated in the hemocytes of mutants. Downregulation of the JNK pathway in hemocytes inhibited <i>Tot</i> induction, leading to enhanced tumor growth. These results suggest that <i>upd3</i> expression in hemocytes depends on the Eiger-JNK pathway. We propose that after Eiger activates the JNK pathway in hemocytes present on the tumor, cells expressing Upd3 are recruited to the FB. Upd3 then activates JAK/STAT to induce the expression of antitumor proteins. This study highlights the intricate communication between tissues via blood cells during tumor suppression.