The loss of epithelial Smad4 drives immune evasion via CXCL1 while displaying vulnerability to combinatorial immunotherapy in gastric cancer

SMAD4 is frequently mutated and inactivated in human gastric cancer (GC). Although the epithelial cellautonomous functions of Smad4 have been extensively studied, its contribution to tumor immunity is largely undetermined. Here, we report that the loss of Smad4 expression in GC cells endows them with the ability to evade tumor immunity. Unlike their Smad4-proficient counterparts, Smad4-deficient stomach organoids can evade host immunity to form tumors in immunocompetent mice. Smad4-deficient GC cells show expanded CD133+ cancer stem-like cells while suppressing dendritic cell (DC) differentiation and cytotoxic T cells with granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation through a secretome containing CXCL1. Moreover, Smad4 deficiency increases programmed cell death ligand-1 (PD-L1) and decreases 4-1BBL expressions, indicating a change in immunogenicity. Combinatorial immune checkpoint blockade (ICB) of anti-PD-L1 and anti-CTLA-4 or agonistic anti-4-1BB antibodies effectively treats ICB monotherapy-resistant Smad4-deficient allografts, exposing a specific vulnerability. Collectively, these data provide a rational basis for ICB strategies in treating advanced GC with Smad4 deficiency.

Automated summary

This study reveals that Smad4 deficiency in human gastric cancer cells allows them to evade tumor immunity and form tumors. Smad4 deficiency leads to an increase in cancer stem-like cells, suppression of dendritic cell and cytotoxic T cell functions, and accumulation of granulocytic myeloid-derived suppressor cells through CXCL1 secretion. Moreover, Smad4 deficiency alters tumor immunogenicity. Combinatorial immune checkpoint blockade effectively treats Smad4-deficient tumors resistant to monotherapy.