Abstract
To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9’s role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide.[1]
As infiltration of cytotoxic and effector CD8+ T cells increased after genetic depletion and pharmacological inhibition of B-cell lymphoma 9 (BCL9), we investigated the cellular landscape associated with this T cell response in more detail using scRNA-seq data
Since expression of the immune checkpoints PD-1 and programmed cell death-ligand 1 (PD-L1) is correlated with infiltrating immune cells and Bcl[9] depletion is synergistic with anti-PD-1 treatment in mouse tumor models, we studied the relationship among CD226, PD-1, and PDL1 in CRC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and triple-negative breast cancer (TNBC)
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide.[1]. In the last few years, significant new insights into the molecular pathways underlying CRC have provided several new therapeutic options.[2,3,4] despite the advances in chemotherapeutic and combined targeted treatment options, most patients with metastatic CRC still exhibit poor survival. There is still an unmet need for more effective treatments.[5,6] Recently, new therapeutic strategies that reinvigorate the immune response directed towards cancer cells were developed. Some of these have successfully paved their way to the clinic, for instance, immune checkpoint inhibitors directed against programmed cell death protein 1 (PD-1) or cytotoxic T lymphocyte-related protein 4 (CTLA-4) are effective against microsatellite-unstable CRC.[7] significant challenges remain, especially for microsatellite-stable CRC, which is characterized by a poor response to these checkpoint inhibitors.[7]
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