Loss of SHP-1 in CD11c⁺ cells impairs anti-tumor immunity

Tyrosine kinases and phosphatases regulate protein phosphorylation and maintain cellular homeostasis. The phosphoprotein tyrosine phosphatase SHP-1 (encoded by the Ptpn6 gene) has been proposed as an immune checkpoint in CD8⁺ T cells in preclinical models, yet its pharmacological inhibition has shown no efficacy against tumor growth in clinical trials. This suggests that SHP-1 may play opposing roles in different cell types within the tumor microenvironment. Here, we investigated the effect of depleting SHP-1 in CD11c⁺ cells on the anti-tumoral response.

To dissect the specific role of SHP1 in CD11c⁺ antigen-presenting cells, or specifically in conventional type 1 dendritic cells (cDC1s) or macrophages, we subcutaneously inoculated different tumors in ItgaxΔPtpn6, Xcr1ΔPtpn6 and Lyz2ΔPtpn6 mice, respectively. Tumor growth and survival were monitored, and immune infiltrates were analyzed using flow cytometry or scRNA-seq.

Tumor rejection was impaired when SHP-1 was depleted in CD11c⁺ cells, as well as in XCR1⁺ or Lyz2⁺ cells. scRNA-seq analysis revealed that both tumor-associated macrophages and cDC1s exhibited downregulation of interferon response pathways in tumor-bearing ItgaxΔPtpn6 mice compared with controls. Reduced MHC-II expression in tumor-associated macrophages was validated by flow cytometry, supporting impaired antigen presentation in these cells, whereas cDC subsets displayed heterogeneous alterations in co-stimulatory marker expression rather than a defect. Consistent with these findings, flow cytometry analysis showed that ItgaxΔPtpn6 mice injected with MC38 tumor and treated with anti-PD1 displayed a reduction in CD8⁺ IFN-γ cells in comparison with Ptpn6 ^f/f littermates.

These results show that SHP-1 depletion in CD11c⁺ cells impairs anti-tumor immunity and suggest that both cDC1s and macrophages contribute to this effect.