Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.
Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.
复制标题
抑制乳腺癌中的PI 3 K/mTOR通路以增强对乳腺癌中免疫检查点抑制剂的反应。
DOI：
10.3390/ijms22105207
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发表时间：
2021-05-14
影响因子：
5.6
通讯作者：
Richmond A
中科院分区：
文献类型：
--
作者：
Yan C;Yang J;Saleh N;Chen SC;Ayers GD;Abramson VG;Mayer IA;Richmond A
Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
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影响因子：
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作者：
Morgillo F;Della Corte CM;Diana A;Mauro CD;Ciaramella V;Barra G;Belli V;Franzese E;Bianco R;Maiello E;de Vita F;Ciardiello F;Orditura M
通讯作者：
Orditura M
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
64.8
作者：
Ali K;Soond DR;Pineiro R;Hagemann T;Pearce W;Lim EL;Bouabe H;Scudamore CL;Hancox T;Maecker H;Friedman L;Turner M;Okkenhaug K;Vanhaesebroeck B
通讯作者：
Vanhaesebroeck B
影响因子：
50.3
作者：
Schmid MC;Avraamides CJ;Dippold HC;Franco I;Foubert P;Ellies LG;Acevedo LM;Manglicmot JR;Song X;Wrasidlo W;Blair SL;Ginsberg MH;Cheresh DA;Hirsch E;Field SJ;Varner JA
通讯作者：
Varner JA