Absence of PD-L1 on tumor cells is associated with reduced MHC I expression and PD-L1 expression increases in recurrent serous ovarian cancer

Aust, Stefanie; Félix, Sophie; Auer, Katharina; Bachmayr-Heyda, Anna; Kenner, Lukas; Dekan, Sabine; Meier, Samuel M.; Gerner, Christopher; Grimm, Christoph; Pils, Dietmar

doi:10.1038/srep42929

Cited by 61 publications

(55 citation statements)

References 33 publications

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“…However, we cannot exclude an impact of pembrolizumab on other cell types including NK cells. Indeed, NK cell responses can have crucial immunotherapeutic effects upon PD-1/PD-L1 blockade in tumors with low levels of MHC-I expression [31]. Additional studies profiling functional immune cell responses during treatment with ICIs could bring new insights on the mechanism of these new therapies in the remission of cancer and viral diseases.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Blanch-Lombarte

Gálvez

Revollo

et al. 2019

JCM

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Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8 + T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir. Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8 + T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load. Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8 + T-cells expressing HLA-DR + /CD38 + transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8 + T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence. Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8 + T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8 + T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement.

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Section: Discussionmentioning

confidence: 99%

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Blanch-Lombarte

Gálvez

Revollo

et al. 2019

JCM

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“…However, many cancer types exhibit a high incidence of MHC loss and/or low neoantigen burden (10,11), which should render tumor cells refractory to recognition by CD8 + T cells. High levels of PD-L1 expression have been observed in tumors with low MHC I expression (12)(13)(14)(15)(16)(17)(18). Interestingly, some of these cancer types are responsive to PD-1/PD-L1 blockade.…”

Section: Introductionmentioning

confidence: 99%

Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

Hsu¹,

Hodgins²,

Marathe³

et al. 2018

Journal of Clinical Investigation

630

533

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Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

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“…Although some authors 9 have confirmed the observation by Hamanishi et al, 8 others have shown exactly the opposite. [10][11][12] These controversial results have raised several questions regarding the method of determination, which types of cells should be scored for surface PD-L1 expression (tumor cell vs immune infiltrate vs both), and the best cutoff percentage of scored cells with which to determine PD-L1 positivity.…”

Section: Role Of Pd-l1 Expression In Patients With Ovarian Cancermentioning

confidence: 99%

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

González-Martín

Sánchez-Lorenzo

2019

Cancer

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Despite advances in surgery and chemotherapy and the integration of antivascular endothelial growth factor therapy as well as poly(adenosine diphosphate-ribose) polymerase inhibitors into daily clinical practice, epithelial ovarian cancer remains the leading cause of death from gynecological cancer. The incorporation of new therapies with the potential to achieve long-term disease remission is a clear need for patients with ovarian cancer. Immunotherapy with checkpoint inhibitors (CPIs) (antiprogrammed cell death protein 1 [anti-PD-1] or antiprogrammed death-ligand 1 [anti-PD-L1]) has been adopted in several malignancies based on improvements shown with regard to progression-free survival and in particular overall survival. Although there is a solid rationale for the use of CPIs in patients with ovarian cancer, to our knowledge the clinical data presented to date are not very convincing. This article reviews the current data regarding CPIs in patients with ovarian cancer along with the future directions and designs of clinical trials aiming to overcome the low efficacy of CPIs in these individuals. Cancer 2019;125:4616-4622.

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Absence of PD-L1 on tumor cells is associated with reduced MHC I expression and PD-L1 expression increases in recurrent serous ovarian cancer

Cited by 61 publications

References 33 publications

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

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