CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer

Seitz, Stefanie; Dreyer, Tobias; Stange, Christoph; Steiger, Katja; Bräuer, Rosalinde; Scheutz, Leandra; Multhoff, Gabriele; Weichert, Wilko; Kiechle, Marion; Magdolen, Viktor; Bronger, Holger

doi:10.1038/s41416-022-01763-0

Cited by 33 publications

(25 citation statements)

References 52 publications

(67 reference statements)

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“…In the context of the contribution of HRD in ovarian cancer, CXCL10 provides a neoteric perspective on markers of immunotherapy. Improved survival, a preferable anti-PD-L1 therapy caused by the overexpression of CXCL9 in ovarian cancer, determined it as a stable predictive target ( Seitz et al, 2022 ). The role of CETP, CCR7, and SELL in ovarian cancer is less studied.…”

Section: Discussionmentioning

confidence: 99%

The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit

Hou

Qiao²,

Li³

et al. 2023

Front. Genet.

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Ovarian cancer (OC) has the lowest survival rate among gynecologic malignancies. Ectopic lymphocyte aggregates, namely tertiary lymphoid structures (TLSs), have been reported as positive biomarkers for tumor prognosis. However, the related gene signature of tertiary lymphoid structure in ovarian cancer was less understood. Therefore, this study first exhibited the organizational patterns of tertiary lymphoid structure by H&E staining and immunohistochemistry (IHC), and confirmed the improved survival values of tertiary lymphoid structure and quantified tumor-infiltrating lymphocytes (CD20+ B cells and CD8+ T cells) in ovarian cancer patients. Secondly, we collected the genes involved in tertiary lymphoid structure from databases. By the univariate regression analysis, the tertiary lymphoid structure gene signature (CETP, CCR7, SELL, LAMP3, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13) with prognostic value, characteristically of ovarian cancer, was constructed in the TCGA dataset and validated in the GSE140082 dataset. Thirdly, by performing CIBERSORT and Tumor Immune Dysfunction and Exclusion (TIDE) analysis, we found that the high expression of this gene signature was positively correlated with developed immune infiltration and reduced immune escape. The improved IPS score and application in the IMvigor210 dataset received PD-L1 proved the predictive value of immunotherapy for this gene signature. Furthermore, this signature showed a better correlation between tumor mutation burden and classical checkpoint genes. In conclusion, Tertiary lymphoid structure plays important role in tumor immunity and the gene signature can be evaluated as a biomarker for predicting prognosis and guiding immunotherapy in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit

Hou

Qiao²,

Li³

et al. 2023

Front. Genet.

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“…Increased production of CXCL9 and CXCL10 have been shown to be associated with increased tumor immune infiltrates in OC as well as with improved response to therapy in melanoma, ovarian, and breast cancer. [60][61][62] Knockdown of STING in PP4C siRNA transfected OC cells, led to decreased immune cell migration in vitro, underscoring the role of STING in promoting an inflammatory phenotype following DNA damage in PP4-inhibited OC cells. At the protein level, we also found increased expression of several other cytokines including IL-8, TNF-α, CCL2, and MIP3α, that are correlated with the SASP phenotype.…”

Section: Pp4c Knockdown In Tumor Cells Augmented Nk Cell Activation A...mentioning

confidence: 93%

PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling

Raja

Bassoy

et al. 2022

J Immunother Cancer

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BackgroundIncreased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in ovarian cancer (OC), the frequency of responses to immune checkpoint blockade (ICB) therapy in OC is much lower than other cancer types. Recent studies have highlighted that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity, which leads to enhanced responses to ICB. Protein phosphatase 4 (PP4) is a critical regulator of the DDR; however, its potential role in antitumor immunity is currently unknown.ResultsOur results show that the PP4 inhibitor, fostriecin, combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using multiple OC cell lines, we show that PP4 inhibition orPPP4Cknockdown combined with carboplatin triggers inflammatory signaling via Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 1 (STAT1) activation. This resulted in increased expression of the pro-inflammatory cytokines and chemokines:CCL5,CXCL10, andIL-6. In addition,IFNB1expression was increased suggesting activation of the type I interferon response. Conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and natural killer (NK) cells over carboplatin treatment alone. Knockdown of stimulator of interferon genes (STING) in OC cells significantly abrogated the increase in CD8 T-cell migration induced by PP4 inhibition. Co-culture of NK-92 cells and OC cells withPPP4CorPPP4R3Bknockdown resulted in strong induction of NK cell interferon-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of OC resulted in significantly reduced tumor growthin vivo. Tumors with PP4C knockdown had increased infiltration of NK cells, NK T cells, and CD4+T cells. Addition of low dose carboplatin treatment led to increased CD8+T-cell infiltration in PP4C knockdown tumors as compared with the untreated PP4C knockdown tumors.ConclusionsOur work has identified a role for PP4 inhibition in promoting inflammatory signaling and enhanced immune cell effector function. These findings support the further investigation of PP4 inhibitors to enhance chemo-immunotherapy for OC treatment.

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“…When melanoma or ovarian cancer cells overexpressing CXCL9 are s.c. injected into mice, the CD4 and CD8 T-cell recruitment and activation are increased and the tumor growth is slowed down [ 59 , 60 ]. Similarly, the CXCL9/10/11 overexpression in Lewis Lung carcinoma cells increases the CD8 T-cell recruitment and controls the tumor growth alone or in association with an anti-PD-1 Ab [ 61 ].…”

Section: Cd8 T-cell Chemoattraction By Chemokines Released During Icdmentioning

confidence: 99%

Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

Roussot

Ghiringhelli

Rébé

2022

Cells

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The success of anticancer treatments relies on a long-term response which can be mediated by the immune system. Thus, the concept of immunogenic cell death (ICD) describes the capacity of dying cancer cells, under chemotherapy or physical stress, to express or release danger-associated molecular patterns (DAMPs). These DAMPs are essential to activate dendritic cells (DCs) and to stimulate an antigen presentation to CD8 cytotoxic cells. Then, activated CD8 T cells exert their antitumor effects through cytotoxic molecules, an effect which is transitory due to the establishment of a feedback loop leading to T-cell exhaustion. This phenomenon can be reversed using immune checkpoint blockers (ICBs), such as anti-PD-1, PD-L1 or CTLA-4 Abs. However, the blockade of these checkpoints is efficient only if the CD8 T cells are recruited within the tumor. The CD8 T-cell chemoattraction is mediated by chemokines. Hence, an important question is whether the ICD can not only influence the DC activation and resulting CD8 T-cell activation but can also favor the chemokine production at the tumor site, thus triggering their recruitment. This is the aim of this review, in which we will decipher the role of some chemokines (and their specific receptors), shown to be released during ICD, on the CD8 T-cell recruitment and antitumor response. We will also analyze the clinical applications of these chemokines as predictive or prognostic markers or as new targets which should be used to improve patients’ response.

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CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer

Cited by 33 publications

References 52 publications

The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit

The gene signature of tertiary lymphoid structures within ovarian cancer predicts the prognosis and immunotherapy benefit

PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling

Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

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