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  1. Article ; Online: Considerations and Approaches for Cancer Immunotherapy in the Aging Host.

    Ontiveros, Carlos O / Murray, Clare E / Crossland, Grace / Curiel, Tyler J

    Cancer immunology research

    2023  Volume 11, Issue 11, Page(s) 1449–1461

    Abstract: Advances in cancer immunotherapy are improving treatment successes in many distinct cancer types. Nonetheless, most tumors fail to respond. Age is the biggest risk for most cancers, and the median population age is rising worldwide. Advancing age is ... ...

    Abstract Advances in cancer immunotherapy are improving treatment successes in many distinct cancer types. Nonetheless, most tumors fail to respond. Age is the biggest risk for most cancers, and the median population age is rising worldwide. Advancing age is associated with manifold alterations in immune cell types, abundance, and functions, rather than simple declines in these metrics, the consequences of which remain incompletely defined. Our understanding of the effects of host age on immunotherapy mechanisms, efficacy, and adverse events remains incomplete. A deeper understanding of age effects in all these areas is required. Most cancer immunotherapy preclinical studies examine young subjects and fail to assess age contributions, a remarkable deficit given the known importance of age effects on immune cells and factors mediating cancer immune surveillance and immunotherapy efficacy. Notably, some cancer immunotherapies are more effective in aged versus young hosts, while others fail despite efficacy in the young. Here, we review our current understanding of age effects on immunity and associated nonimmune cells, the tumor microenvironment, cancer immunotherapy, and related adverse effects. We highlight important knowledge gaps and suggest areas for deeper enquiries, including in cancer immune surveillance, treatment response, adverse event outcomes, and their mitigation.
    MeSH term(s) Humans ; Aged ; Aging ; Immunotherapy ; Neoplasms ; Immunologic Surveillance ; Treatment Outcome ; Tumor Microenvironment
    Language English
    Publishing date 2023-09-28
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-23-0121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7022: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality.

    Kornepati, Anand V R / Boyd, Jacob T / Murray, Clare E / Saifetiarova, Julia / de la Peña Avalos, Bárbara / Rogers, Cody M / Bai, Haiyan / Padron, Alvaro S / Liao, Yiji / Ontiveros, Carlos / Svatek, Robert S / Hromas, Robert / Li, Rong / Hu, Yanfen / Conejo-Garcia, Jose R / Vadlamudi, Ratna K / Zhao, Weixing / Dray, Eloïse / Sung, Patrick /
    Curiel, Tyler J

    Cancer research

    2022  Volume 82, Issue 11, Page(s) 2156–2170

    Abstract: BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of ... ...

    Abstract BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection. Genetic depletion of tumor PD-L1 reduced homologous recombination, increased nonhomologous end joining, and elicited synthetic lethality to PARP inhibitors olaparib and talazoparib in vitro in some, but not all, BRCA1 wild-type tumor cells. In vivo, genetic depletion of tumor PD-L1 rendered olaparib-resistant tumors sensitive to olaparib. In contrast, anti-PD-L1 immune checkpoint blockade neither enhanced olaparib synthetic lethality nor improved its efficacy in vitro or in wild-type mice. Tumor PD-L1 did not alter expression of BRCA1 or its cofactor BARD1 but instead coimmunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TANK-binding kinase 1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collectively, these data define immune-dependent and immune-independent effects of PARP inhibitor treatment and genetic tumor PD-L1 depletion. Moreover, they implicate a tumor cell-intrinsic, immune checkpoint-independent function of PD-L1 in cancer cell BRCA1-mediated DNA damage repair with translational potential, including as a treatment response biomarker.
    Significance: PD-L1 upregulates BRCA1-mediated homologous recombination, and PD-L1-deficient tumors exhibit BRCAness by manifesting synthetic lethality in response to PARP inhibitors, revealing an exploitable therapeutic vulnerability and a candidate treatment response biomarker. See related commentary by Hanks, p. 2069.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; B7-H1 Antigen/genetics ; BRCA1 Protein/genetics ; Cell Line, Tumor ; DNA Repair ; Humans ; Mice ; Neoplasms/drug therapy ; Neoplasms/genetics ; Phthalazines/pharmacology ; Phthalazines/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Synthetic Lethal Mutations
    Chemical Substances Antineoplastic Agents ; B7-H1 Antigen ; BRCA1 Protein ; CD274 protein, human ; Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2022-03-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-21-2076
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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