PD-L1 Blockade by Atezolizumab Downregulates Signaling Pathways Associated with Tumor Growth, Metastasis, and Hypoxia in Human Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, which shows resistance to common breast cancer therapies, as it lacks the expression of the most common breast cancer targets. Therefore, TNBC treatment remains a challenge. Targeting programmed cell death-ligand 1 (PD-L1) by monoclonal antibodies (mAbs), for example, atezolizumab, has revolutionized the treatment for various cancer types. However, the therapeutic efficacy of targeting PD-L1 in TNBC is currently under investigation. In this study, we investigated the molecular mechanisms by which the human TNBC cell line MDA-MB-231, expressing PD-L1, responds to atezolizumab, using RNA-Seq. Transcriptome analysis revealed 388 upregulated and 362 downregulated genes in response to atezolizumab treatment. The expression of selected genes, from RNA-Seq data, was subsequently validated using RT-qPCR in the MDA-MB-231 and MDA-MB-468 TNBC cells following atezolizumab treatment. Bioinformatics analysis revealed that atezolizumab downregulates genes promoting cell migration/invasion and metastasis, epithelial-mesenchymal transition (EMT), cell growth/proliferation/survival, and hypoxia. On the contrary, genes associated with apoptosis and DNA repair were upregulated in response to atezolizumab treatment. Gene set enrichment analyses revealed that a significant number of these genes are related to the NF-kB, PI3K/Akt/mTOR, MAPK, and CD40 signaling pathways. Using functional assays, we confirmed that atezolizumab increases MDA-MB-231 cell apoptosis/necrosis, and reduces their proliferation and viability. Collectively, our findings provide novel insights into the molecular mechanisms/signaling pathways by which atezolizumab exerts inhibitory effects on TNBC, thereby inhibiting EMT/metastasis, tumor growth/survival, and the induction of hypoxia.

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

“…While most pronounced effects were in fact seen in the combination therapy and thus interpretable as synergistic, the monotherapy itself modulated the tumor microenvironment. Anti-PD-L1 treatment induced genes relevant for autophagy and downregulated NF-κB-signaling, which is in line with data from a recent trial on triple negative breast cancer cells, treated with Atezolizumab [45]. Upon vaccination, matrix remodeling/metastasis-related genes and genes of the Wnt-and TGF-signaling were downregulated.…”

Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

“…Nevertheless, the role of PD-L2 in cancer progression is still unclear. On another note, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are crucial oncogenic pathways that regulate PD-L1 expression [30]. Transcriptional PD-L1 is not only regulated by the PI3K pathway [31], but also regulated by signal transducer and activator of transcription 3 (STAT3) [32], nuclear factor kappa B (NF-κB) [33], and B-cell CLL/lymphoma 3 (Bcl3) proto-oncogene [34].…”

PI3K abrogation using pan PI3K inhibitor BKM120 give rise to a weighty anti-cancer effect on AML-derived KG-1 cells by inducing apoptosis and G2/M arrest

“…Our results showed that BKM120 upregulated the mRNA expressions of proapoptotic genes and diminished the transcription of antiapoptotic target genes of NF-κB ( Figure 5A). Based on our findings and with reference to the considerable studies pointing to the tight crosstalk between NF-κB and the PI3K pathway [24], we examined the effect of NF-κB suppression on the anticancer impact of the inhibitor. Our results showed that the suppression of NF-κB using a well-known proteasome inhibitor, bortezomib, amplified the repressive effect of the PI3K inhibition on KG-1 cell survival ( Figure 5B).…”