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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]

A common theme across multiple successful immunotherapies for cancer is the recognition of tumor-specific mutations (neoantigens) by T cells. The rapid discovery of such antigen responses could lead to improved therapies through the adoptive transfer of T cells engineered to express neoantigen-reactive T cell receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. Screening of TCRs selected by the signature allows us to identify neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+ T cells. Because of the small number of samples analyzed (4 patients), generalizability remains to be tested. However, this approach can enable the quick identification of neoantigen-reactive TCRs and expedite the engineering of personalized neoantigen-reactive T cells for therapy. [Display omitted] • T cells in fresh NSCLC tumor were analyzed by CITE-seq with TCR-seq • Neoantigen-reactive T cells are CD39 protein+, CXCL13 +, and high-frequency clonotype • The signature can identify both CD4 and CD8 neoantigen-reactive T cells • This method can expedite the personalized neoantigen-reactive T cell therapy The discovery of T cell receptors (TCRs) that recognize tumor-specific neoantigens can lead to improved therapies through the adoptive transfer of T cells engineered to express these TCRs. Here, Hanada et al. design a signature of neoantigen-reactive T cells that enables the rapid identification of both CD4 and CD8 neoantigen-reactive TCRs. [ABSTRACT FROM AUTHOR]