Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity
HNSCC is the sixth most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lympho...
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| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/953 |
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| author | Kelvin Anderson Nathan Ryan Anastasia Alkhimovitch Arham Siddiqui Steve Oghumu |
| author_facet | Kelvin Anderson Nathan Ryan Anastasia Alkhimovitch Arham Siddiqui Steve Oghumu |
| author_sort | Kelvin Anderson |
| collection | DOAJ |
| description | HNSCC is the sixth most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lymphoid immune cell function, it is essential to understand how PI3K p110γ inhibition affects the anti-tumor immune response independent of tumor cells. To elucidate PI3K p110γ function in HNSCC, we employed an orthotopic mouse model using poorly immunogenic and aggressive cell line MOC2 on <i>Pik3cg<sup>−/−</sup></i> mice. We observed that wild-type and <i>Pik3cg<sup>−/−</sup></i> mice displayed similar rates of HNSCC tumor growth and metastasis after 20 days following tumor injection. T-cell infiltration and intrinsic T-cell responses to MOC2 oral tumors were comparable between wild-type and <i>Pik3cg<sup>−/−</sup></i> mice. Interestingly, the immune response of tumor-bearing <i>Pik3cg<sup>−/−</sup></i> mice was marked by increased anti-tumor cytotoxic molecules (IFN-γ, IL-17)) by T-cells and immune checkpoint marker (PD-L1, PD-1) expression by myeloid cells and T-cells compared to tumor-bearing wild-type mice. Taken together, our findings demonstrate that inhibition of PI3K p110γ modulates tumor-associated immune cells, which likely potentiates HNSCC treatment when used in combination with selective checkpoint inhibitors. |
| first_indexed | 2024-03-09T00:34:07Z |
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| id | doaj.art-fa0940e19d0d47c1a7119b4600aa6b4c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:34:07Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fa0940e19d0d47c1a7119b4600aa6b4c2023-12-11T18:21:44ZengMDPI AGCancers2072-66942021-02-0113595310.3390/cancers13050953Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low ImmunogenicityKelvin Anderson0Nathan Ryan1Anastasia Alkhimovitch2Arham Siddiqui3Steve Oghumu4Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USADepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USADepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USADepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USADepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USAHNSCC is the sixth most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lymphoid immune cell function, it is essential to understand how PI3K p110γ inhibition affects the anti-tumor immune response independent of tumor cells. To elucidate PI3K p110γ function in HNSCC, we employed an orthotopic mouse model using poorly immunogenic and aggressive cell line MOC2 on <i>Pik3cg<sup>−/−</sup></i> mice. We observed that wild-type and <i>Pik3cg<sup>−/−</sup></i> mice displayed similar rates of HNSCC tumor growth and metastasis after 20 days following tumor injection. T-cell infiltration and intrinsic T-cell responses to MOC2 oral tumors were comparable between wild-type and <i>Pik3cg<sup>−/−</sup></i> mice. Interestingly, the immune response of tumor-bearing <i>Pik3cg<sup>−/−</sup></i> mice was marked by increased anti-tumor cytotoxic molecules (IFN-γ, IL-17)) by T-cells and immune checkpoint marker (PD-L1, PD-1) expression by myeloid cells and T-cells compared to tumor-bearing wild-type mice. Taken together, our findings demonstrate that inhibition of PI3K p110γ modulates tumor-associated immune cells, which likely potentiates HNSCC treatment when used in combination with selective checkpoint inhibitors.https://www.mdpi.com/2072-6694/13/5/953PI3KHNSCCimmune checkpointp110γPD-L1 |
| spellingShingle | Kelvin Anderson Nathan Ryan Anastasia Alkhimovitch Arham Siddiqui Steve Oghumu Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity Cancers PI3K HNSCC immune checkpoint p110γ PD-L1 |
| title | Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity |
| title_full | Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity |
| title_fullStr | Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity |
| title_full_unstemmed | Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity |
| title_short | Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity |
| title_sort | inhibition of pi3k isoform p110γ increases both anti tumor and immunosuppressive responses to aggressive murine head and neck squamous cell carcinoma with low immunogenicity |
| topic | PI3K HNSCC immune checkpoint p110γ PD-L1 |
| url | https://www.mdpi.com/2072-6694/13/5/953 |
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