Akt Inhibition Is Associated With Favorable Immune Profile Changes Within the Tumor Microenvironment of Hormone Receptor Positive, HER2 Negative Breast Cancer

Abstract

Background: The PI3K/Akt/mTOR pathway in part impacts tumorigenesis through modulation of host immune activity. To assess the effects of Akt inhibition on the tumor micro-environment (TME), we analyzed tumor tissue from patients with operable hormone receptor positive, HER2 negative breast cancer (BC) treated on a presurgical trial with the Akt inhibitor MK-2206. Methods: Quantitative multiplex immunofluorescence (qmIF) was performed using CD3, CD8, CD4, FOXP3, CD68, and pancytokeratin on biopsy and surgical specimens of MK-2206 and untreated, control patients. nanoString was performed on surgical specimens to assess mRNA expression from MK-2206-treated vs. control patients. Results: Increased CD3+CD8+ density was observed in post vs. pre-treatment tissue in the MK-2206-treated vs. control patients (87 vs. 0.2%, p < 0.05). MK-2206 was associated with greater expression of interferon signaling genes (e.g., IFI6, p < 0.05) and lower expression of myeloid genes (CD163, p < 0.05) on differential expression and gene set enrichment analyses. Greater expression of pro-apoptotic genes (e.g., BAD) were associated with MK-2206 treatment (p < 0.05). Conclusion: Akt inhibition in operable BC was associated with a favorable immune profile in the TME, including increased CD3+CD8+ density and greater expression of interferon genes. Additional studies are warranted, as this may provide rationale for combining Akt inhibition with immunotherapy.

Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis

“…Recently, it has been found that TME plays important role in the initiation and development of cancer, especially in breast cancer 36 , 37 . Besides to cancer cell biology, the immune microenvironment (IME) that surrounding cancer cells, has also been found to affect tumorgenesis and metastasis of breast cancer.…”

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

“…Recent studies have also demonstrated the effect of the Akt inhibitors on TME in cancer patients. For instance, in HER2 negative breast cancer patients, two oral doses of the Akt inhibitor, MK-2206, were associated with a favorable immune profile in TME, including increased CD3 + CD8 + density and greater expression of interferon genes [ 80 ]. However, there is no study yet assessing the impact of Akt inhibition on TME in HCC patients.…”

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

“…AKT can inhibit TCR/LEF/β-catenin and FOXO transcription, which are required for the function of T cell memory ( Lazarevic et al, 2013 ). Specifically, AKT inhibition can led to a favorable immune profile in the breast tumor microenvironment, including an increased density of CD3+CD8+ cells and better expression of interferon genes, providing a rationale for using AKT inhibition plus immunotherapy combination ( Marks et al, 2020 ). Correspondingly, the PI3Kβ inhibitor AZD8186 enhanced anticancer efficacy by combining with anti-PD1 Ab in PTEN-deficient xenografts ( Owusu-Brackett et al, 2020 ).…”