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  • 1
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    Online Resource
    Abstract A216: Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. A216-A216
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A216-A216
    Abstract: T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is effective only in a minority of patients. The basis for T-cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T-cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T-cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “stem-like exhausted” T-cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T-cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T-cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Debattama R. Sen, Brian C. Miller, Rose Al Abosy, Kevin Bi, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen D. Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Yamini V. Virkud, Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A216.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A216
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2732517-9
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  • 2
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    PI3K activated tumors evade tumor immunity by promoting an inhibitory myeloid microenvironment
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 58.17-58.17
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 58.17-58.17
    Abstract: Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. Here we use an in vivo screen of known cancer-associated somatic mutations in immunocompetent mouse tumor models treated with checkpoint blockade to identify oncogenes that confer immune evasion. We found that a catalytically active mutation in Phospho-Inositol 3 Kinase (PI3K), PIK3CA c.3140A & gt;G (H1047R) confers selective growth advantage after immunotherapy. Pharmacologic PI3K inhibition resensitizes mutant tumors to immunotherapy with anti-PD-1. The tumor microenvironment (TME) in PIK3CA H1047R-expressing tumors has fewer infiltrating CD8+ T cells after immunotherapy but is enriched for immune inhibitory myeloid cells. Inhibition of myeloid infiltration in PIK3CA H1047R tumors results in increased sensitivity to PD-1 checkpoint blockade. Thus PI3K has a role in tumor immune evasion mediated by establishment of an inhibitory myeloid microenvironment in addition to its well-described, cell-intrinsic oncogenic role. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. More generally, our data suggest a rationale to combine PI3K inhibition with immunotherapy of PI3KCA mutant tumors.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.58.17
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
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  • 3
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    Abstract 706: In vivo tumor-associated mutation screen identifies PI3K activation as a mechanism of resistance to PD-1 blockade
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 706-706
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 706-706
    Abstract: Known genomic correlates of response to immunotherapy do not perfectly predict clinical outcome, supporting the existence of unknown mechanisms of resistance to tumor immunity. We hypothesize that somatic, cancer-associated mutations account for heterogeneity in spontaneous response to tumors and response to immunotherapy. We have undertaken a systematic in vivo screen to identify mechanisms of resistance to tumor immunity in order to define a comprehensive set of therapeutic targets and provide biomarkers of sensitivity to immunotherapy. Mouse tumor cell lines (MC38 colon carcinoma or B16 melanoma) were engineered to express a library of barcoded open reading frames (ORFs) mutagenized to encode known cancer-associated somatic mutations. Tumor-bearing animals were treated with anti-PD-1. A mutation in Phospho-Inositol 3 Kinase (PI3K), PIK3CA c.3140A & gt;G, increased in representation in anti-PD-1 treated tumors but not in immunodeficient animals, suggesting that activity of the mutant allele conferred selective growth advantage in the setting of tumor immunity. This mutation encodes a constitutively active mutant catalytic domain, PIK3CA H1047R. MC38 tumors homogeneously expressing H1047R and implanted into wild-type mice failed to respond to anti-PD-1 therapy, while tumors expressing a control gene regressed. Pharmacologic PI3K inhibition resensitized tumors to treatment with anti-PD-1. PD-1-treated PIK3CA H1047R tumors had fewer infiltrating CD8+ T cells as measured by immunohistochemistry and flow cytometry. Single-cell RNA-seq of tumor-infiltrating immune cells revealed a population of myeloid cells expressing known immune inhibitory proteins that differentially enriched in PIK3CA H1047R-expressing tumors. Our data suggest that PI3K has, in addition to its well-described oncogenic role, a role in tumor immune evasion mediated by establishment of an inhibitory myeloid microenvironment. As such, activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy, and these studies provide a rationale for therapeutic combination trials of PI3K inhibition with checkpoint blockade and other myeloid-targeting immunotherapies. Citation Format: Natalie B. Collins, Brian C. Miller, Kevin Bi, Rose Al Abosy, Kathleen Yates, Yashaswi Shrestha, John Doench, Jesse Boehm, W Nicholas Haining. In vivo tumor-associated mutation screen identifies PI3K activation as a mechanism of resistance to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 706.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-706
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 2701: Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2701-2701
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2701-2701
    Abstract: T cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The basis for T cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells that have a distinct regulatory state. Progenitor exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy but this occurs without reversion of their exhausted epigenetic state. Human melanomas contain CD8+ T cells with a progenitor exhausted phenotype and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini V. Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade [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 2701.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2701
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Abstract 6362: Overcoming resistance to immunotherapy due to loss of antigen presentation
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6362-6362
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6362-6362
    Abstract: Resistance to immune checkpoint inhibitors represents a major therapeutic challenge, as only 40% of patients with melanoma (and less with other tumor types) have a long-term response to anti-PD-1 therapy. Resistance can arise because of somatic mutations in cancer cells that allow evasion of T cell-mediated killing. One commonly acquired resistance mutation in melanoma, loss of beta-2 microglobulin (B2m), prevents T cell killing by hiding cancer cells from CD8+ T cell recognition. To understand the failed immune response against resistant tumors, we used single-cell RNA-seq to characterize tumor-infiltrating immune cells in antigen presentation-deficient human melanoma biopsies and CRISPR-modified mouse melanoma tumors. Our data demonstrate an increase in immunosuppressive M2-like macrophages and absence of CD8+ T cells in B2m-null tumors. To overcome this resistance, we treated tumor-bearing mice with CD40 agonist antibody, which promotes differentiation of macrophages towards a pro-inflammatory phenotype and increases dendritic cell priming of CD8+ T cells. Treatment with CD40 agonist reduced tumor growth and improved tumor clearance in B2m-null melanoma and colorectal cancer models. To determine how CD40 agonist treatment works, we depleted different immune populations from the tumor microenvironment. We hypothesized that by depleting M2 macrophages, CD40 agonist treatment would remove an immunosuppressive brake to allow natural killer (NK) cells to kill tumor cells lacking MHC expression. To our surprise, NK cells were not required for the efficacy of CD40 agonist. Instead CD8+ T cells were required, even though the CD8+ T cells cannot directly recognize the tumor cells. scRNA-seq identified a transcriptionally unique state of CD8+ T cells that is recruited to the tumor microenvironment after CD40 agonist treatment. These CD8+ T cells produce IFNγ, which is required for the efficacy of CD40 agonist treatment. These data demonstrate that CD8+ T cells, a key mediator of anti-tumor immunity, can still be recruited to control tumors deficient in antigen presentation. More broadly, they suggest that strategies to activate CD8+ T cells may be effective even in the context of acquired resistance to checkpoint inhibitor therapy. Citation Format: Brian C. Miller, Yacine Choutri, Rose Al Abosy, Amy Huang, Emily K. Cox, Matthew P. Zimmerman, Wan Lin Chong, Katherine J. Vietor, Jenna Collier, Sarah A. Weiss, Debattama Sen, W. Nicholas Haining, Arlene H. Sharpe. Overcoming resistance to immunotherapy due to loss of antigen presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6362.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6362
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract PR6: Disrupting enhancers within the core epigenetic program of exhaustion improves T-cell responses and enhances tumor control
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 3_Supplement ( 2020-03-01), p. PR6-PR6
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 3_Supplement ( 2020-03-01), p. PR6-PR6
    Abstract: T-cell exhaustion describes an acquired dysfunction common in settings of cancer and chronic viral infection. Despite clinical efforts to rescue exhaustion, the fundamental mechanisms specifying this state, and the potential for reprogramming exhausted T cells, remain poorly understood. We profiled accessible chromatin in chronic viral infection to show that exhausted CD8+ cells acquire a state-specific landscape of enhancers that profoundly differs from functional memory. Critically, CD8+ tumor-infiltrating lymphocytes shared significant epigenetic and transcriptional features with chronic viral infection, suggesting that T-cell exhaustion is a fundamental adaptation to settings of chronic stimulation. Comparison of mouse cells to those isolated from patients infected with HCV or HIV showed that the core epigenetic program of exhaustion is conserved across species. Importantly, curative therapy, which reduces viral antigen load, as well as anti-PD-1 immunotherapy, which reduces inhibitory T-cell signaling, failed to reverse the exhausted epigenetic profile. T-cell exhaustion is therefore a stable epigenetic state that is not rescued by common treatment modalities. We then sought new strategies to modulate T-cell exhaustion. We used Cas9-mediated genome editing to generate a novel mouse strain with germline deletion of a core exhaustion-associated enhancer near PD-1. We observed 2- to 3-fold enrichment in vivo of PD-1 enhancer-null cells over control cells in chronic infection, suggesting that CD8+ T cells in these mice might be less prone to exhaustion. PD-1 enhancer-null mice also exhibited slower tumor growth and increased survival when challenged with B16-ova melanoma. The establishment of a core program of T-cell exhaustion and increased insight into its epigenetic modulation has crucial implications for the future of immunotherapy and rational engineering of T cells for clinical use. This abstract is also being presented as Poster A3. Citation Format: Debattama R. Sen, Sarah A. Weiss, Brian C. Miller, Pierre Tonnerre, Rose Al Abosy, Kathleen B. Yates, Kevin Bi, Martin W. Lafleur, David Wolski, Lauer Georg, Arlene H. Sharpe, W. Nicholas Haining. Disrupting enhancers within the core epigenetic program of exhaustion improves T-cell responses and enhances tumor control [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR6.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM19-PR6
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 7
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    Abstract A83: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 3_Supplement ( 2020-03-01), p. A83-A83
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 3_Supplement ( 2020-03-01), p. A83-A83
    Abstract: T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The mechanisms by which anti-PD-1 therapy acts on exhausted T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. Exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells with critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy. Melanoma patients with a higher percentage of progenitor exhausted cells have a longer duration of response to checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Jeffrey J. Ishizuka, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A83.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM19-A83
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 8
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    Online Resource
    PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 3 ( 2022-03), p. e003402-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 3 ( 2022-03), p. e003402-
    Abstract: Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion. Results We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A 〉 G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8 + T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade. Conclusions PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-003402
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 9
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    Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
    Springer Science and Business Media LLC ; 2021
    In:  Nature Immunology Vol. 22, No. 8 ( 2021-08), p. 1020-1029
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 22, No. 8 ( 2021-08), p. 1020-1029
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-021-00979-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2026412-4
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  • 10
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    PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity
    Springer Science and Business Media LLC ; 2019
    In:  Nature Immunology Vol. 20, No. 10 ( 2019-10), p. 1335-1347
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 20, No. 10 ( 2019-10), p. 1335-1347
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-019-0480-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2026412-4
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