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
Perlmutter Cancer Center, NYU Langone Health, New York, NY, United States.
Department of Pediatrics, Pediatric Hematology/Oncology and Medicine, Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, United States.
Front Oncol. 2020 Jun 16;10:968. doi: 10.3389/fonc.2020.00968. eCollection 2020.
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. 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. Increased CD3+CD8+ density was observed in post vs. pre-treatment tissue in the MK-2206-treated vs. control patients (87 vs. 0.2%, < 0.05). MK-2206 was associated with greater expression of interferon signaling genes (e.g., , < 0.05) and lower expression of myeloid genes (, < 0.05) on differential expression and gene set enrichment analyses. Greater expression of pro-apoptotic genes (e.g., ) were associated with MK-2206 treatment ( < 0.05). 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.
PI3K/Akt/mTOR信号通路部分通过调节宿主免疫活性影响肿瘤发生。为评估Akt抑制对肿瘤微环境（TME）的影响，我们分析了在一项术前试验中接受Akt抑制剂MK - 2206治疗的可手术激素受体阳性、HER2阴性乳腺癌（BC）患者的肿瘤组织。对MK - 2206治疗组和未治疗的对照组患者的活检及手术标本，使用CD3、CD8、CD4、FOXP3、CD68和全细胞角蛋白进行定量多重免疫荧光（qmIF）检测。对手术标本进行nanoString检测，以评估MK - 2206治疗组与对照组患者的mRNA表达。在MK - 2206治疗组与对照组患者中，治疗后组织相对于治疗前组织，观察到CD3 + CD8 + 密度增加（87%对0.2%，P < 0.05）。在差异表达和基因集富集分析中，MK - 2206与干扰素信号基因的更高表达（例如，P < 0.05）和髓系基因的更低表达（P < 0.05）相关。促凋亡基因（例如）的更高表达与MK - 2206治疗相关（P < 0.05）。可手术BC中的Akt抑制与TME中良好的免疫特征相关，包括CD3 + CD8 + 密度增加和干扰素基因的更高表达。鉴于此可能为Akt抑制与免疫治疗联合应用提供理论依据，有必要开展进一步研究。
