Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy.

Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8+ T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC. [Display omitted] • CD49f is an underrated yet highly potent TIC marker in HCC • CD49f-high TICs form a reciprocal loop with neutrophils in the TME • Neutrophils confer CD155-dependent immune privilege to TICs to evade immune killing • Anti-PD-1/CD155 effectively eliminates TICs and demonstrate promising efficacy in HCC Yang et al. identify CD49f as a prominent tumor-initiating cells (TIC) marker in HCC and reveal a reciprocal loop between CD49f-high TICs and neutrophils that promotes tumor immune evasion by enhancing CD155 expression. They further demonstrate that blocking CD155 can improve the effectiveness of anti-PD-1 therapy, offering new therapeutic insights against HCC. [ABSTRACT FROM AUTHOR]