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Andrzej Lewiński - One of the best experts on this subject based on the ideXlab platform.

  • The role of phosphoinositide 3-kinase subunits in chronic thyroiditis
    Thyroid research, 2012
    Co-Authors: Katarzyna Wojciechowska-durczynska, Kinga Krawczyk-rusiecka, Anna Cyniak-magierska, Arkadiusz Zygmunt, Stanisław Sporny, Andrzej Lewiński
    Abstract:

    Background The risk of neoplastic transformation in patients with chronic thyroiditis (Hashimoto’s thyroiditis – HT) is slightly increased. Genetic background of this observation is still unclear. PI3K isoforms are linked with inflammatory and neoplastic processes, thus they appear to be interesting subjects of a research in this respect. The aim of our study was to assess the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes expression levels in HT.

  • Riedel's thyroiditis - a case report with genes' expression studies
    Thyroid Research, 2012
    Co-Authors: Katarzyna Wojciechowska-durczynska, Stanisław Sporny, Adam Durczyński, Janusz Strzelczyk, Andrzej Lewiński
    Abstract:

    Background Genetic background of Riedel's thyroiditis remains unknown. Herein, we describe our results of studies on genes expression levels in Riedel's thyroiditis. Case report and genetic findings We report the case of 48-year old woman with Riedel's thyroiditis who has presented unusual course of disease with non-specific cervical discomfort, though as with no pain and/or no compression symptoms. After surgery, thyroid specimens were quantitatively evaluated, regarding PIK3CA, PIK3CD, PIK3CG, Tg, TGFB1, THRB, COL1, CDKN1C, CDH3 and CACNA2D2 genes expression levels, by real-time PCR in the ABI PRISM^® 7500 Sequence Detection System. Out of 10 above genes, in 2 cases the expression was higher than in respective Controls of unchanged thyroid tissue. In the remaining 8 cases, expression in question became comparable or lower as in Controls. Discussion The association between increased expression levels of PIK3CA and CDH3 genes and Riedel's thyroiditis is not well-defined. However, the increased expression of PIK3CA and CDH3 genes in our case report and in previous studies of other authors on various malignancies may suggest possible molecular relation between Riedel's thyroiditis and certain neoplastic processes, the relation of which requires further genetic evaluation. It is to be stressed that gene expression studies in Riedel's thyroiditis are difficult to perform, mainly due to fibrosis, resulting in scarce thyroid specimens and - in consequence - small amount of genetic material.

Judith A. Varner - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 1077: Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12
    Cancer Chemistry, 2020
    Co-Authors: Hideyuki Takahashi, Ryan M. Shepard, Ann Shih, Marc A. Paradise, Sang Min Lee, Cristina Flores-arenas, William Kim, Judith A. Varner
    Abstract:

    We previously reported that macrophage PI3kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition polarizes tumor-associated macrophages (TAMs) into pro-inflammatory macrophages, leading to the recruitment and activation of intratumoral CD8+ T cells, tumor growth inhibition and anti-tumor memory (Kaneda et al 2016). In the present study, we elucidated the role of PI3Kγ in the control of T cell immune responses, including activation, memory generation and exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). High-dimensional single-cell analysis including single-cell RNA sequencing and mass cytometry of HPV+ HNSCC tumors revealed significant differences in intratumoral immune cell clusters in HPV+ HNSCC tumors from WT and PIK3CG−/− mice. Primary tumors from PIK3CG−/− mice exhibited more pro-inflammatory TAMs, more activated CD8+ T cells and fewer exhausted T cells than in tumors from WT mice. Both tumor- and spleen-derived T cells from PIK3CG−/− mice exhibited more IFNγ expression than those from WT mice; this increase could be reversed by the neutralization of IL-12 and MHCII. We observed significantly more effector memory T cells in spleens of PIK3CG−/− mice than WT mice; accordingly, adoptive transfer of PIK3CG−/− but not WT splenic T cells conferred tumor resistance onto naive WT mice, indicating that PI3Kγ inhibition promotes T cell mediated immunological memory. In summary, PIK3CG−/− mice exhibited more activated T cells, T cell mediated immune responses and T cell memory than WT mice, resulting significant and sustained suppression of tumor growth. These results indicate that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Ryan M. Shepard, Marc A. Paradise, Sang Min Lee, Ann Shih, Cristina Flores-Arenas, William Kim, Judith A. Varner. Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1077.

  • Abstract A86: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion
    Cancer immunology research, 2020
    Co-Authors: Hideyuki Takahashi, Paulina Pathria, Ryan M. Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner
    Abstract:

    Introduction: Tumor-associated macrophages promote immunosuppressive microenvironment in head and neck squamous cell carcinoma (HNSCC). We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. The aim of the present study was to investigate the effect of PI3Kγ inhibition on T-cell immune response, especially on T-cell memory and exhaustion status using mouse models of HNSCC. Materials and Methods: Wild-type (WT) or PIK3CG-/- 6- to 8-week-old male syngeneic C57Bl/6J mice were implanted with HPV+ MEER tumor cells (mouse HPV+ HNSCC cell line) by subcutaneous injection. Tumors, draining lymph nodes and spleens were isolated, then analyzed using flow cytometry or mass cytometry. Mice that completely cleared tumors were reinjected with tumor cells and tumor growth was monitored. CD90.2+ T cells or CD19+ B cells that were harvested from spleens of WT or PIK3CG-/- tumor-inoculated mice were mixed 1:1 with viable tumor cells and injected into the flanks of naive WT mice. Results: Mice lacking PI3Kγ exhibited suppressed growth of implanted HPV+ MEER tumors. The proportion of T cells, especially CD8+ T cells, significantly increased in tumors from Pik3c-/- mice. T cells from PIK3CG-/- tumors expressed significantly more granzyme B and less T-cell exhaustion markers. The proportion of CD8+ effector memory T cells significantly increased in spleens from PIK3CG-/- mice. Mice that were implanted with both tumor cells and T cells from spleens of tumor-bearing PIK3CG-/- mice exhibited significant suppression of tumor growth. All mice that had previously cleared tumors dramatically suppressed tumor growth when rechallenged with tumor cells and remained cancer-free. Conclusion:PIK3CG-/- mice showed more activated T-cell immune response and T-cell memory than WT, resulting in significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy might enhance the activity of checkpoint inhibitors through the activation of T-cell immune response in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ryan Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A86.

  • Abstract 1513: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages
    Immunology, 2019
    Co-Authors: Hideyuki Takahashi, Paulina Pathria, Ryan M. Shepard, Ann Shih, Marc A. Paradise, Judith A. Varner
    Abstract:

    We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition repolarizes tumor-associated macrophages, leading to downregulation of immune suppressive factors such as Arginase and IL10 and upregulation of IL12 and other pro-inflammatory cytokines. This results in recruitment and activation of intratumoral CD8+ T cells, as well as induction of immunological memory (Kaneda et al 2016). In the present study, we investigated the effect of PI3Kγ inhibition on T cell immune responses, including T cell memory induction and T cell exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). We found that PIK3CG−/− mice cleared implanted HPV+ HNSCC tumors; when re-challenged with tumor cells, these mice rapidly cleared secondary tumors and remained cancer-free. The proportion of T cells, especially CD8+ T cells, significantly increased in primary tumors from PIK3CG−/− mice. These CD8+ T cells expressed significantly more granzyme B and interferon and less T cell exhaustion markers than T cells from WT animals, indicating that PI3Kγ inhibition in macrophages results in T cell activation. We found that anti-tumor activity was transferable, as adoptive transfer of splenic T cells from PIK3CG−/− mice to naive WT mice suppressed tumor growth. Accordingly, PIK3CG−/− mice with primary or secondary tumors exhibited more splenic CD62L-CD44+ CD8+ effector memory T cells than WT mice. In summary, PIK3CG−/− mice exhibit a more activated T cell immune response and T cell memory than WT mice, resulting significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ann Shih, Ryan M. Shepard, Marc A. Paradise, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1513.

Xin Zhao - One of the best experts on this subject based on the ideXlab platform.

  • Genomic sequencing and editing revealed the GRM8 signaling pathway as potential therapeutic targets of squamous cell lung cancer.
    Cancer letters, 2018
    Co-Authors: Panpan Zhang, Bin Kang, Guoyun Xie, Yue Shen, Xin Zhao
    Abstract:

    Abstract The study sought to explore novel genetic aberration driving squamous cell lung carcinoma (LUSC). The whole exome (WES), whole genome (WGS) and target region (TS) sequencings and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes (FGFR2, GRM1,PIK3CG, PIK3CA,ZFHX4, CSMD3, GRM8) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes (CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through CRISPR-Cas9 system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of Metabotropic glutamate receptor 8 (GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer carrying GRM8 activating variants.

Katarzyna Wojciechowska-durczynska - One of the best experts on this subject based on the ideXlab platform.

  • The role of phosphoinositide 3-kinase subunits in chronic thyroiditis
    Thyroid research, 2012
    Co-Authors: Katarzyna Wojciechowska-durczynska, Kinga Krawczyk-rusiecka, Anna Cyniak-magierska, Arkadiusz Zygmunt, Stanisław Sporny, Andrzej Lewiński
    Abstract:

    Background The risk of neoplastic transformation in patients with chronic thyroiditis (Hashimoto’s thyroiditis – HT) is slightly increased. Genetic background of this observation is still unclear. PI3K isoforms are linked with inflammatory and neoplastic processes, thus they appear to be interesting subjects of a research in this respect. The aim of our study was to assess the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes expression levels in HT.

  • Riedel's thyroiditis - a case report with genes' expression studies
    Thyroid Research, 2012
    Co-Authors: Katarzyna Wojciechowska-durczynska, Stanisław Sporny, Adam Durczyński, Janusz Strzelczyk, Andrzej Lewiński
    Abstract:

    Background Genetic background of Riedel's thyroiditis remains unknown. Herein, we describe our results of studies on genes expression levels in Riedel's thyroiditis. Case report and genetic findings We report the case of 48-year old woman with Riedel's thyroiditis who has presented unusual course of disease with non-specific cervical discomfort, though as with no pain and/or no compression symptoms. After surgery, thyroid specimens were quantitatively evaluated, regarding PIK3CA, PIK3CD, PIK3CG, Tg, TGFB1, THRB, COL1, CDKN1C, CDH3 and CACNA2D2 genes expression levels, by real-time PCR in the ABI PRISM^® 7500 Sequence Detection System. Out of 10 above genes, in 2 cases the expression was higher than in respective Controls of unchanged thyroid tissue. In the remaining 8 cases, expression in question became comparable or lower as in Controls. Discussion The association between increased expression levels of PIK3CA and CDH3 genes and Riedel's thyroiditis is not well-defined. However, the increased expression of PIK3CA and CDH3 genes in our case report and in previous studies of other authors on various malignancies may suggest possible molecular relation between Riedel's thyroiditis and certain neoplastic processes, the relation of which requires further genetic evaluation. It is to be stressed that gene expression studies in Riedel's thyroiditis are difficult to perform, mainly due to fibrosis, resulting in scarce thyroid specimens and - in consequence - small amount of genetic material.

Hideyuki Takahashi - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 1077: Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12
    Cancer Chemistry, 2020
    Co-Authors: Hideyuki Takahashi, Ryan M. Shepard, Ann Shih, Marc A. Paradise, Sang Min Lee, Cristina Flores-arenas, William Kim, Judith A. Varner
    Abstract:

    We previously reported that macrophage PI3kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition polarizes tumor-associated macrophages (TAMs) into pro-inflammatory macrophages, leading to the recruitment and activation of intratumoral CD8+ T cells, tumor growth inhibition and anti-tumor memory (Kaneda et al 2016). In the present study, we elucidated the role of PI3Kγ in the control of T cell immune responses, including activation, memory generation and exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). High-dimensional single-cell analysis including single-cell RNA sequencing and mass cytometry of HPV+ HNSCC tumors revealed significant differences in intratumoral immune cell clusters in HPV+ HNSCC tumors from WT and PIK3CG−/− mice. Primary tumors from PIK3CG−/− mice exhibited more pro-inflammatory TAMs, more activated CD8+ T cells and fewer exhausted T cells than in tumors from WT mice. Both tumor- and spleen-derived T cells from PIK3CG−/− mice exhibited more IFNγ expression than those from WT mice; this increase could be reversed by the neutralization of IL-12 and MHCII. We observed significantly more effector memory T cells in spleens of PIK3CG−/− mice than WT mice; accordingly, adoptive transfer of PIK3CG−/− but not WT splenic T cells conferred tumor resistance onto naive WT mice, indicating that PI3Kγ inhibition promotes T cell mediated immunological memory. In summary, PIK3CG−/− mice exhibited more activated T cells, T cell mediated immune responses and T cell memory than WT mice, resulting significant and sustained suppression of tumor growth. These results indicate that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Ryan M. Shepard, Marc A. Paradise, Sang Min Lee, Ann Shih, Cristina Flores-Arenas, William Kim, Judith A. Varner. Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1077.

  • Abstract A86: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion
    Cancer immunology research, 2020
    Co-Authors: Hideyuki Takahashi, Paulina Pathria, Ryan M. Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner
    Abstract:

    Introduction: Tumor-associated macrophages promote immunosuppressive microenvironment in head and neck squamous cell carcinoma (HNSCC). We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. The aim of the present study was to investigate the effect of PI3Kγ inhibition on T-cell immune response, especially on T-cell memory and exhaustion status using mouse models of HNSCC. Materials and Methods: Wild-type (WT) or PIK3CG-/- 6- to 8-week-old male syngeneic C57Bl/6J mice were implanted with HPV+ MEER tumor cells (mouse HPV+ HNSCC cell line) by subcutaneous injection. Tumors, draining lymph nodes and spleens were isolated, then analyzed using flow cytometry or mass cytometry. Mice that completely cleared tumors were reinjected with tumor cells and tumor growth was monitored. CD90.2+ T cells or CD19+ B cells that were harvested from spleens of WT or PIK3CG-/- tumor-inoculated mice were mixed 1:1 with viable tumor cells and injected into the flanks of naive WT mice. Results: Mice lacking PI3Kγ exhibited suppressed growth of implanted HPV+ MEER tumors. The proportion of T cells, especially CD8+ T cells, significantly increased in tumors from Pik3c-/- mice. T cells from PIK3CG-/- tumors expressed significantly more granzyme B and less T-cell exhaustion markers. The proportion of CD8+ effector memory T cells significantly increased in spleens from PIK3CG-/- mice. Mice that were implanted with both tumor cells and T cells from spleens of tumor-bearing PIK3CG-/- mice exhibited significant suppression of tumor growth. All mice that had previously cleared tumors dramatically suppressed tumor growth when rechallenged with tumor cells and remained cancer-free. Conclusion:PIK3CG-/- mice showed more activated T-cell immune response and T-cell memory than WT, resulting in significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy might enhance the activity of checkpoint inhibitors through the activation of T-cell immune response in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ryan Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A86.

  • Abstract 1513: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages
    Immunology, 2019
    Co-Authors: Hideyuki Takahashi, Paulina Pathria, Ryan M. Shepard, Ann Shih, Marc A. Paradise, Judith A. Varner
    Abstract:

    We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition repolarizes tumor-associated macrophages, leading to downregulation of immune suppressive factors such as Arginase and IL10 and upregulation of IL12 and other pro-inflammatory cytokines. This results in recruitment and activation of intratumoral CD8+ T cells, as well as induction of immunological memory (Kaneda et al 2016). In the present study, we investigated the effect of PI3Kγ inhibition on T cell immune responses, including T cell memory induction and T cell exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). We found that PIK3CG−/− mice cleared implanted HPV+ HNSCC tumors; when re-challenged with tumor cells, these mice rapidly cleared secondary tumors and remained cancer-free. The proportion of T cells, especially CD8+ T cells, significantly increased in primary tumors from PIK3CG−/− mice. These CD8+ T cells expressed significantly more granzyme B and interferon and less T cell exhaustion markers than T cells from WT animals, indicating that PI3Kγ inhibition in macrophages results in T cell activation. We found that anti-tumor activity was transferable, as adoptive transfer of splenic T cells from PIK3CG−/− mice to naive WT mice suppressed tumor growth. Accordingly, PIK3CG−/− mice with primary or secondary tumors exhibited more splenic CD62L-CD44+ CD8+ effector memory T cells than WT mice. In summary, PIK3CG−/− mice exhibit a more activated T cell immune response and T cell memory than WT mice, resulting significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ann Shih, Ryan M. Shepard, Marc A. Paradise, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1513.