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.
Highlights
Targeted therapies have changed the treatment landscape of breast cancer (BC); until recently, BC was generally considered a minimally “immunogenic” malignancy and less likely to benefit from novel immunotherapeutic agents
As preclinical data exist to supports activity of phosphatidylinositol 3 kinase (PI3K) targeted agents on the immune microenvironment, the goal of this study was to assess the impact of Akt inhibition on the tumor micro-environment (TME) of HR+/HER2− BC in samples collected in a pre-surgical clinical trial
By Quantitative multiplex immunofluorescence (qmIF) and targeted genomic expression analysis, we confirmed in human breast cancer specimens the biologic activity of MK-2206, with well-described changes in gene expression of known targets of the PI3K/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway as well as marked indirect immune related effects of Akt inhibition on the TME including an increase in CTL density as well as greater expression of interferon related genes and lower expression of myeloid genes
Summary
Targeted therapies have changed the treatment landscape of breast cancer (BC); until recently, BC was generally considered a minimally “immunogenic” malignancy and less likely to benefit from novel immunotherapeutic agents. Of the BC subtypes, triple negative breast cancer (TNBC) has demonstrated an impressive response rate to immune checkpoint blockade combined with chemotherapy [2]. In addition to direct anti-neoplastic activity, there is growing evidence that agents targeting the PI3K/Akt/mTOR pathway have indirect anti-tumor activity mediated through the host immune response [10]. 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. 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
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