CD8+ T-cell lymphocytes infiltration predict clinical outcomes in Wilms’ tumor

Mardanpour, Keykhosro; Rahbar, Mahtab; Mardanpour, Sourena; Mardanpour, Nyousha; Rezaei, Mansour

doi:10.1177/1010428320975976

Cited by 20 publications

(15 citation statements)

References 39 publications

(40 reference statements)

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“…All studies underline the presence of an immunosuppressive microenvironment in Wilms tumor. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 The cell infiltrate is usually detected in the stromal component of the tumor, and the most abundant cells are tumor-associated macrophages (TAMs). 19 , 24 , 25 , 29 There has been an attempt to correlate the presence of such cells to clinicopathological features of WT.…”

Section: Immune Cell Infiltrationmentioning

confidence: 99%

“…Despite the general lack of a CD8+ immune T cell infiltrate, Mardanpour et al. 30 recently found that higher CD8+ tumor-infiltrating lymphocyte counts at the invasive margins were correlated with lower tumor recurrency rates. In particular, early-stage tumors were found to present significantly higher TILs both in the center and in the invasive border of the tumor.…”

Section: Immune Cell Infiltrationmentioning

confidence: 99%

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Systematic review of the immunological landscape of Wilms tumors

Palmisani

Kovar

Kager

et al. 2021

Molecular Therapy - Oncolytics

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Results of immunotherapy in childhood solid cancer have been so far, with the exception of neuroblastoma, quite disappointing. Lack of knowledge of the immune contexture of these tumors may have contributed to the failure of immunotherapies so far. Here, we systematically reviewed the literature regarding the immunology of Wilms tumor (WT), one of the most frequent pediatric solid tumors of the abdomen. In Wilms tumor patients the high cure rate of >90%, achieved by the combination of surgery and radio-chemotherapy, is at the expense of a high early and late toxicity. Moreover, treatment-resistant entities, such as diffuse anaplastic tumors or recurrent disease, still pose unsolved clinical problems. Successful immunotherapy could represent a novel and possibly less-toxic treatment option. Employing the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) method of literature search, we analyzed the current knowledge of the immunological landscape of Wilms tumors in terms of tumor microenvironment, prognostic implications of single biomarkers, and immunotherapy response.

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Section: Immune Cell Infiltrationmentioning

confidence: 99%

Section: Immune Cell Infiltrationmentioning

confidence: 99%

Systematic review of the immunological landscape of Wilms tumors

Palmisani

Kovar

Kager

et al. 2021

Molecular Therapy - Oncolytics

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“… 11 Additionally, Wilms tumors with lower CD8 + TIL scores are associated with larger size, increased invasiveness and metastasis, and shorter overall patient survival. 12 These results suggest that when T cell inflammation does occur in Wilms tumors, it can be associated with improved prognosis. A deeper characterization of pediatric tumors, especially those with low TMB and low T cell inflammation, may shed light on tumor-intrinsic mechanisms of immune evasion relevant to adult tumors as well.…”

Section: Introductionmentioning

confidence: 88%

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Higgs

Bao

Hatogai

et al. 2022

J Immunother Cancer

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BackgroundA T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.MethodsRNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy.ResultsAmong the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2+ tumor cells and CD8+ T cells. Additionally, melanomas with high MSH2+ tumor cell numbers were largely non-responders to anti-PD-1 therapy.ConclusionsIncreased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.

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“…One potential limitation of immune checkpoint inhibition is that pediatric solid tumors exhibit low immunogenicity due to low mutational burden and/or downregulation of MHC-I expression, leading to low tumor infiltration of activated T and NK cells. Multiple publications have demonstrated the variable proliferation of these tumor infiltrating lymphocytes (TILs) in pediatric histologies (and significant variation between individuals) including in neuroblastoma [13], Wilms tumor [14], germ cell tumors [15], brain tumors [16], and osteosarcoma [17]. Interestingly, the degree of tumor cell differentiation in neuroblastoma appears to correlate with degree of TIL infiltration as well as increased MHC-I expression and improved outcome [13].…”

Section: Immune Checkpoint Inhibitors (Pd-1 Pd-l1 Ctla-4)mentioning

confidence: 99%

Immunotherapies for Pediatric Solid Tumors: A Targeted Update

Gupta

Cripe

2021

Pediatr Drugs

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There are encouraging signs in our collective progress to leverage the immune system to treat pediatric cancers. Here, we summarize interim successes in cancer immunotherapy and opportunities to translate from the adult world to pediatrics, and highlight challenges that could benefit from additional development, focusing on solid tumors. Just a decade ago, other than antibodies targeting disialoganglioside (GD2) in neuroblastoma, pediatric cancer immunotherapy was mostly relegated to obscure preclinical studies in a few academic labs. Today there are numerous clinical trials of a variety of antibody, cellular, gene, and viral therapies and vaccines designed to either promote antitumor immunity or specifically attack validated immunotherapy targets. Understanding those targets and their pediatric relevance is paramount. While much work is underway to evaluate the utility of numerous immunologic targets, the lack of regulatory approvals is emblematic of the challenges that remain. Herein we focus our review on the most promising targeted immunotherapies in clinical trials for children. Key PointsTreatment of pediatric solid tumors is starting to benefit from a variety of cell-surface targets and new approaches to attack those targets.The most promising of these targets include: immune checkpoints, GD2, B7-H3, HER2, and CD47. Future directions will likely include combinations of therapies, biomarkers to assess success, the creation of more antibody-drug conjugates, and further breakdown of regulatory barriers.

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CD8+ T-cell lymphocytes infiltration predict clinical outcomes in Wilms’ tumor

Cited by 20 publications

References 39 publications

Systematic review of the immunological landscape of Wilms tumors

Systematic review of the immunological landscape of Wilms tumors

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Immunotherapies for Pediatric Solid Tumors: A Targeted Update

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