Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer
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 effe...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/10/5207 |
| _version_ | 1797534078072782848 |
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| author | Chi Yan Jinming Yang Nabil Saleh Sheau-Chiann Chen Gregory D. Ayers Vandana G. Abramson Ingrid A. Mayer Ann Richmond |
| author_facet | Chi Yan Jinming Yang Nabil Saleh Sheau-Chiann Chen Gregory D. Ayers Vandana G. Abramson Ingrid A. Mayer Ann Richmond |
| author_sort | Chi Yan |
| collection | DOAJ |
| description | 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<sup>+</sup> T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8<sup>+</sup> 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<sup>+</sup> 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. |
| first_indexed | 2024-03-10T11:24:32Z |
| format | Article |
| id | doaj.art-0f72cf8c86ae470c82c49f9672274a3e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:24:32Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0f72cf8c86ae470c82c49f9672274a3e2023-11-21T19:44:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210520710.3390/ijms22105207Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast CancerChi Yan0Jinming Yang1Nabil Saleh2Sheau-Chiann Chen3Gregory D. Ayers4Vandana G. Abramson5Ingrid A. Mayer6Ann Richmond7Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USADepartment of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USADepartment of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USADepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USAObjectives: 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<sup>+</sup> T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8<sup>+</sup> 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<sup>+</sup> 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.https://www.mdpi.com/1422-0067/22/10/5207PI3K/mTORbreast cancerimmune checkpoint inhibitorcytotoxic T cells |
| spellingShingle | Chi Yan Jinming Yang Nabil Saleh Sheau-Chiann Chen Gregory D. Ayers Vandana G. Abramson Ingrid A. Mayer Ann Richmond Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer International Journal of Molecular Sciences PI3K/mTOR breast cancer immune checkpoint inhibitor cytotoxic T cells |
| title | Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer |
| title_full | Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer |
| title_fullStr | Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer |
| title_full_unstemmed | Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer |
| title_short | Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer |
| title_sort | inhibition of the pi3k mtor pathway in breast cancer to enhance response to immune checkpoint inhibitors in breast cancer |
| topic | PI3K/mTOR breast cancer immune checkpoint inhibitor cytotoxic T cells |
| url | https://www.mdpi.com/1422-0067/22/10/5207 |
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