TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remains poorly explored. Here we combined extensive immunolabeling of human tissues with in-silico analysis of pan-cancer transcriptomic datasets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In-silico analysis of a pan-cancer dataset revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had higher expression of the immunosuppressive molecules TREM2, IL10 and TGFβ as compared to TLSTIM4+MΦ. By analyzing a scRNA-seq dataset of tumor-associated myeloid cells we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene-signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene-signature positively correlate with better prognosis. Together these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotype and tissue localization and that may have opposing roles in tumor immunity.

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