PAK4 as a cancer immune-evasion target

Gajewski, Thomas F.; Fessler, Jessica

doi:10.1038/s43018-019-0012-z

Cited by 15 publications

(14 citation statements)

References 12 publications

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“…S3), a result consistent with a previous publication [29]. A recent study suggests that PAK4 is enriched in nonresponding tumor biopsies [30], and we also observed that PAK4 was significantly more highly expressed in the immune-suppressed subtype than in the immuneactivated subtype (P = 0.037, Fig. S3).…”

Section: Two Distinct Immunophenotypes Highlighted By Different Microenvironmental Conditionssupporting

confidence: 92%

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Immune response drives outcomes in prostate cancer: implications for immunotherapy

Meng

Zhou

et al. 2020

Molecular Oncology

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The heterogeneity of the immune microenvironment leads to different responses in immune checkpoint blockade therapy. We aimed to propose a robust molecular classification system to investigate the relevance of the immune microenvironment subtype and prognosis of prostate cancer patients, as well as the therapeutic response to immune checkpoint blockade therapy. A total of 1,557 prostate cancer patients were enrolled, including 69 real‐world samples from our institute (titled the AHMU‐PC cohort). The non‐negative matrix factorization algorithm was employed to virtually microdissect patients. The immune enrichment was characterized by a high enrichment of T cell‐, B cell‐, NK cell‐, and macrophage‐associated signatures, by which patients were subclassified into nonimmune and immune classes. Subsequently, the immune class was dichotomized into immune‐activated and immune‐suppressed subtypes based on the stromal signature, represented by the activation of WNT/TGF‐β, TGF‐β1, and C‐ECM signatures. Approximately 14.9% to 24.3% of patients belonged to the immune‐activated subtype, which was associated with favorable recurrence‐free survival outcomes. In addition, patients in the immune‐activated subtype were predicted to benefit more from anti‐PD‐1/PD‐L1 therapy. In conclusion, our study identifies a novel immune molecular classifier that is closely related to clinical prognosis and provides novel insights into immunotherapeutic strategies for prostate cancer patients.

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Section: Two Distinct Immunophenotypes Highlighted By Different Microenvironmental Conditionssupporting

confidence: 92%

“…biopsies [30], and we also observed that PAK4 was significantly more highly expressed in the immune-suppressed subtype than in the immune-activated subtype (P = 0.037, Supplementary Figure 3). In addition, we found that the tumor-infiltrating Treg (TITR) signature (P < 0.01) and…”

Section: Accepted Articlesupporting

confidence: 52%

Immune response drives outcomes in prostate cancer: implications for immunotherapy

Meng

Zhou

et al. 2020

Molecular Oncology

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“…Interestingly, we found PAK4 as one of the predictive genes for NK_Res_Bulk. PAK4 was recently introduced as a target in cancer immune evasion as its expression was inversely correlated with CD8 T cell infiltration and ICB response in melanoma, and PAK4 overexpression correlated with an activated Wnt-β-catenin pathway [56, 57].…”

Section: Resultsmentioning

confidence: 99%

The ratio of exhausted to resident infiltrating lymphocytes is prognostic for colorectal cancer patient outcome

Foroutan

Molania

Pfefferle

et al. 2020

Preprint

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Immunotherapy success in colorectal cancer (CRC) is mainly limited to patients whose tumours exhibit high microsatellite instability (MSI). However, there is variability in treatment outcomes within this group, which is in part driven by the frequency and characteristics of tumour infiltrating immune cells. Indeed, the presence of specific infiltrating immune cell subsets has been shown to correlate with immunotherapy responses and is in many cases prognostic of treatment outcome. Tumour-infiltrating lymphocytes (TILs) can undergo distinct differentiation programs such as acquire features of tissue-residency or exhaustion, a process during which T cells upregulate inhibitory receptors such as PD-1 and loose functionality. While residency and exhaustion programs of CD8 T cells are relatively well-studied, these programs have only recently been appreciated in CD4 T cells and remain largely unknown in tumour-infiltrating natural killer (NK) cells. In this study, we use single cell RNA-seq data to identify signatures of residency and exhaustion in CRC infiltrating lymphocytes, including CD8, CD4 and NK cells. We then test these signatures in independent single cell data from tumour and normal tissue infiltrating immune cells. Further, we use versions of these signatures adapted for bulk RNA-seq data to identify a list of tumour intrinsic mutations associated with residency and exhaustion from TCGA data. Finally, using two independent transcriptomic data sets from patients with colon adenocarcinoma, we show that combinations of these signatures, in particular NK signatures, as well as tumour-associated signatures, such as TGF-β signalling, are associated with distinct survival outcomes in colorectal cancer patients.

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“…PD-1/PD-L1 is the most successful immune checkpoint target of tumor immunotherapy and its blocking antibodies have been found to exert significant clinic therapeutic effects in various tumors, thus having been widely prescribed by tumor patients ( Gajewski and Fessler, 2020 ). However, continuous treatment of PD-1/PD-L1 blockers also suffers from drug resistance, which is in large part due to lack of immune cells or poor T cell infiltration in surrounding tumor tissues.…”

Section: The Role Of P21-activated Kinase 4 In Cancermentioning

confidence: 99%

Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents

Xie

et al. 2022

Front. Pharmacol.

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The p21-activated kinase 4 (PAK4) is a member of the PAKs family. It is overexpressed in multiple tumor tissues. Pharmacological inhibition of PAK4 attenuates proliferation, migration, and invasion of cancer cells. Recent studies revealed that inhibition of PAK4 sensitizes immunotherapy which has been extensively exploited as a new strategy to treat cancer. In the past few years, a large number of PAK4 inhibitors have been reported. Of note, the allosteric inhibitor KPT-9274 has been tested in phase Ⅰ clinic trials. Herein, we provide an update on recent research progress on the PAK4 mediated signaling pathway and highlight the development of the PAK4 small molecular inhibitors in recent 5 years. Meanwhile, challenges, limitations, and future developmental directions will be discussed as well.

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PAK4 as a cancer immune-evasion target

Cited by 15 publications

References 12 publications

Immune response drives outcomes in prostate cancer: implications for immunotherapy

Immune response drives outcomes in prostate cancer: implications for immunotherapy

The ratio of exhausted to resident infiltrating lymphocytes is prognostic for colorectal cancer patient outcome

Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents

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