ANXA1 Promotes Tumor Immune Evasion by Binding PARP1 and Upregulating Stat3-Induced Expression of PD-L1 in Multiple Cancers

Abstract

The deregulation of annexin A1 (ANXA1), a regulator of inflammation and immunity, leads to cancer growth and metastasis. However, whether ANXA1 is involved in cancer immunosuppression is still unclear. Here, we report that ANXA1 knockdown (i) dramatically downregulates programmed cell death-ligand 1 (PD-L1) expression in breast cancer, lung cancer, and melanoma cells; (ii) promotes T cell-mediated killing of cancer cells in vitro; and (iii) inhibits cancer immune escape in immune-competent mice via downregulating PD-L1 expression and increasing the number and killing activity of CD8+ T cells. Mechanistically, ANXA1 functioned as a sponge molecule for interaction of PARP1 and Stat3. Specifically, binding of ANXA1 to PARP1 decreased PARP1’s binding to Stat3, which reduced poly(ADP-ribosyl)ation and dephosphorylation of Stat3 and thus, increased Stat3’s transcriptional activity, leading to transcriptionally upregulated expression of PD-L1 in multiple cancer cells. In clinical samples, expression of ANXA1 and PD-L1 was significantly higher in breast cancer, non-small cell lung cancer, and skin cutaneous melanoma compared to corresponding normal tissues and positively correlated in cancer tissues. Moreover, using both ANXA1 and PD-L1 proteins for predicting efficacy of anti-PD-1 immunotherapy and patient prognosis were superior to using individual proteins. Our data suggest that ANXA1 promotes cancer immune escape via binding PARP1 and upregulating Stat3-induced expression of PD-L1, that ANXA1 is a potential new target for cancer immunotherapy, and combination of ANXA1 and PD-L1 expression is a potential marker for predicting efficacy of anti-PD-1 immunotherapy in multiple cancers.

Comprehensive analysis of the relationship between ubiquitin-specific protease 21 (USP21) and prognosis, tumor microenvironment infiltration, and therapy response in colorectal cancer

“…Using mRNA sequencing data from public databases, we performed differential expression analysis, identifying molecules exhibiting pronounced expression variances as potential downstream targets of USP21. Notably, a majority of these molecules are implicated in regulating TME [25][26][27][28][29][30][31][32][33]. Functional enrichment analysis showed functional pathways associated with immune activation that correlate with low USP21.…”

“…4C). Notably, PYGO2, UBQLN4, and ANXA1 have been associated with responsiveness to tumor immune checkpoint blockade (ICB) therapy [25][26][27], while B4GAL and MDM2 are implicated in regulating CD8 + T cell function and tumor growth [28,29]. Additionally, UBE2Q1, ARNTL2, CLK2, and EMP1 have been shown to participate in modulating the TME in various tumors [30][31][32][33].…”

An overview of the regulatory role of annexin A1 in the tumor microenvironment and its prospective clinical application (Review)

“…In addition, ANXA1 has been confirmed to mediate increased expression of programmed cell death ligand 1 (PD-L1) by upregulating the phosphorylation of AKT and STAT3 in cancer cells (95,96). As an immune checkpoint, PD-L1 can interact with programmed cell death 1 (PD-1) to inactivate CTLs and trigger the immune escape of tumor cells (97).…”