Erratum: Corrigendum: PI3Kγ is a molecular switch that controls immune suppression

Kaneda, Megan M.; Messer, Karen; Ralainirina, Natacha; Li, Hongying; Leem, Christopher J.; Gorjestani, Sara; Woo, Gyunghwi; Nguyen, Abraham V.; Figueiredo, Camila C.; Foubert, Philippe; Schmid, Michael C.; Pink, Melissa; Winkler, David G.; Rausch, Matthew; Palombella, Vito J.; Kutok, Jeffery L.; McGovern, Karen; Frazer, Kelly A.; Wu, Xuefeng; Karin, Michael; Šášik, Roman; Cohen, Ezra E.W.; Varner, Judith A.

doi:10.1038/nature21026

Cited by 39 publications

(25 citation statements)

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“…Third, treatment with ENT+anti–PD-1 significantly decreased expression of genes within the mTOR pathway. It has previously been shown that inhibition of mTORC1 can disrupt the immunosuppressive abilities of myeloid cells, including Arg-1 protein expression (54,55). Therefore, it is likely that PD-1 inhibition also contributes to the observed MDSC dysfunction through decreased mTOR signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Christmas

Rafie

Hopkins

et al. 2018

Cancer Immunology Research

169

144

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Immune checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TME’s such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs) whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti–PD-1, anti–CTLA-4, or both, significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic cancer mouse models. Using flow cytometry, gene expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic-MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B–producing CD8+ T effector cells in mice treated with combination therapy. Gene expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers.

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Section: Discussionmentioning

confidence: 99%

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Christmas

Rafie

Hopkins

et al. 2018

Cancer Immunology Research

169

144

View full text Add to dashboard Cite

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“…These antitumor effects were attributed to suppression of PIK3CG in macrophages leading to suppression of cytotoxic T cells and not due to decreased PIK3CG in tumor cells. Genetic or pharmacologic downregulation of PIK3CG altered the transcriptional program of tumor-infiltrating macrophages to promote cytotoxic T cell infiltration of pancreatic tumors, thus extending survival of the mice (21, 54, 55). However, unlike ablation of Pik3ca in KPC tumor cells, all of the animals with downregulated PIK3CG eventually died from pancreatic cancer progression (21).…”

Section: Discussionmentioning

confidence: 99%

Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

Sivaram

McLaughlin

Han

et al. 2019

Journal of Clinical Investigation

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The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in Kras G12D /Trp53 R172H -driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca -null tumors implanted in T cell–deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen–experienced T cells eliminated Pik3ca -null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector AKT increased the expression of MHC class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca -null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

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“…These antitumor effects were attributed to suppression of PIK3CG in macrophages leading to suppression of cytotoxic T cells and not due to decreased PIK3CG in tumor cells. Genetic or pharmacologic downregulation of PIK3CG altered the transcriptional program of tumor-infiltrating macrophages to promote cytotoxic T cell infiltration of pancreatic 17 tumors, thus extending survival of the mice [21,59,60]. However, unlike ablation of Pik3ca in KPC tumor cells, all of the animals with downregulated PIK3CG eventually died from pancreatic cancer progression [21].…”

Section: Discussionmentioning

confidence: 99%

PIK3CA inKras^G12D/Trp53^R172HTumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

Sivaram

et al. 2019

Preprint

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The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in Kras G12D /Trp53 R172H -driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increases the expression of MHC Class I and CD80 on tumor cells. These changes contribute to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. These results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer. 3 SIGNIFICANCE PIK3CA-AKT signaling in pancreatic cancer cells limits T cell infiltration and clearance of tumors by suppressing the surface expression of MHC Class I and CD80. Targeting the PIK3CA-AKT pathway in tumor cells provides a new avenue for discovery of novel pancreatic cancer immunotherapies.

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Erratum: Corrigendum: PI3Kγ is a molecular switch that controls immune suppression

Cited by 39 publications

References 1 publication

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

PIK3CA inKras^G12D/Trp53^R172HTumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

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Erratum: Corrigendum: PI3Kγ is a molecular switch that controls immune suppression

Cited by 39 publications

References 1 publication

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs

Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

PIK3CA inKrasG12D/Trp53R172HTumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

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Product

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PIK3CA inKras^G12D/Trp53^R172HTumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer