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

Authors: Marks, Douglas K.; Gartrell, Robyn D.; El Asmar, Margueritta; Boboila, Shuobo; Hart, Thomas; Lu, Yan; Pan, Qingfei; Yu, Jiyang; Hibshoosh, Hanina; Guo, Hua; Andreopoulou, Eleni; Wiechmann, Lisa; Crew, Katherine; Sparano, Joseph; Hershman, Dawn; Connolly, Eileen; Saenger, Yvonne; Kalinsky, Kevin

Online: https://www.frontiersin.org/article/10.3389/fonc.2020.00968/full

Issue: Front Oncol. 2020 Jun 16;10:968.


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.

Keywords: AKT inhibitor; MK-2206; breast cancer; pre-surgical; quantitative multiplex immunofluorescence; tumor immunobiology; tumor microenvironment.