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Targeting CD37 promotes phagocytosis against multi cancer cell

ABSTRACT: Macrophages play vital roles in innate and adaptive immunity, and their indispensable functions are accomplished by phagocytosis and antigen presentation. Great efforts have been made to explore the potential mechanism of action of potential phagocytosis checkpoints. However, the use of a systematic checkpoint scanning strategy is far from satisfactory. We thus established an in vitro phagocytosis assay using primary healthy donors’ macrophages and breast cancer cells. Equal numbers of cells were sorted and subjected to ribosome profiling, and immune system-specific checkpoints were ultimately identified. CD37 was dramatically downregulated in phagocytic macrophages and targeting CD37 with a specific antibody promoted phagocytosis of multiple cancer cells. Tumorous macrophage migration inhibitory factor (MIF) directly binds to CD37 and promotes the recruitment of SHP1. Targeting CD37 enhances the efficacy of CD47 in vivo and in vitro. In all, our study identified a previously unidentified phagocytosis checkpoint and provided new potential for precise therapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jie Li

PROVIDER: PXD061433 | iProX | Wed Jun 04 00:00:00 BST 2025

REPOSITORIES: iProX

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Targeting CD37 promotes macrophage-dependent phagocytosis of multiple cancer cell types and facilitates tumor clearance in mice.

Gao Xinya X Zhang Jing J Zhang Hui H Liu Xin X Zeng Bo B Wang Huijin H Zhang Hanbing H Lui Weng-Onn WO Hui Xiaoyan X Miao Hongming H Li Jie J

Nature communications 20250718 1

Macrophages play vital roles in innate and adaptive immunity, and their functions are mediated via phagocytosis and antigen presentation. Despite the effort to identify phagocytic checkpoints and explore their mechanism of action, current checkpoint-scanning strategies cannot provide a complete and systematic list of such immune checkpoints. Here, we perform in vitro phagocytosis assays using primary healthy donor macrophages co-cultured with breast cancer cells followed by ribosome profiling of ...[more]

PMID: 40675974

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Project description:Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10-5) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10-6) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.

Dataset Information

Targeting CD37 promotes phagocytosis against multi cancer cell

Publications

Targeting CD37 promotes macrophage-dependent phagocytosis of multiple cancer cell types and facilitates tumor clearance in mice.

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