PD-L1(+) Macrophages Activated by Tumor-Derived GM-CSF Induce CD8(+) T Cell Exhaustion in Hepatocellular Carcinoma Outstanding Award

Background: The efficacy of treatment based on immune checkpoint inhibitors (ICI) is limited in patients with hepatocellular carcinoma (HCC) due to the immunosuppressive microenvironment. Tumor-associated macrophages (TAMs) influence cancer progression and ICI response through immunosuppression. We previously reported that TAM contributes to tumor progression (J Immunol. 2018, Biomed phar. 2023). This study explored the spatial interactions between PD-L1(+) TAMs and CD8(+) T cells in resected HCC tissues.
Methods: mIHC (CD8, CD68, CD163, PD-L1, DAPI) was performed on 113 resected HCC specimens. Cell distribution in the tumor/border/non-tumor area were determined using inForm software. Interaction variable was calculated with phenoptr®. The mouse HCC cell line, BNL, transfected with GM-CSF vector was injected into BALB/c mice. Anti-GM-CSF and PD-L1 antibodies were injected.
Results: A higher interaction variable of PD-L1(+) TAMs and CD8(+) T cells was associated with increased recurrence rates, worse prognosis, and positively correlated with tumor cell-derived GM-CSF expression. In vitro, GM-CSF upregulated expressions of Pd-l1 and chemokines in macrophages and impaired CD8(+) T cell antitumor activity. In HCC mouse model, GM-CSF enhanced PD-L1(+) TAMs and CD8(+) T cell interactions, promoting tumor growth through immunosuppression. Anti-GM-CSF therapy disrupted this interaction, and combination with anti-PD-L1 synergistically boosted antitumor immunity.