Gene expression markers of Tumor Infiltrating Leukocytes

Danaher, Patrick; Warren, Sarah; Dennis, Lucas; D’Amico, Leonard A.; White, Andrew; Disis, Mary L.; Geller, Melissa A.; Odunsi, Kunle; Beechem, Joseph M.; Fling, Steven P.

doi:10.1186/s40425-017-0215-8

Cited by 658 publications

(603 citation statements)

References 32 publications

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“…Upon closer examination, all immune response categories appeared to be upregulated after treatment with sipuleucel-T, with genes involved in leukocyte functions exhibiting the highest level of increase in expression (Figure 1B). Immune cell scores of lymphocytes infiltrated into the tumor microenvironment were calculated by nSolver software based on gene expression levels normalized to housekeeping genes 6 The scores of total T cells, cytotoxic CD8 T cells, and helper T cells were significantly increased after sipuleucel-T treatment (p = 0.02, 0.05 and <0.01, respectively), and there was a trend for increased total B cells post-treatment (p = 0.11, Figure 1C). When examining specific CD4 T cell subsets, the immune cell score of the Th1 subtype was significantly increased after treatment (p = 0.03), while the immune cell scores of Th2, Th17 and Treg subtypes were unchanged (Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

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Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

et al. 2018

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Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry. Sipuleucel-T treatment was associated with increased expression of Th1-associated genes, but not Th2-, Th17 – or Treg-associated genes. Post-treatment tumor tissues with high CD8+T cell infiltration was associated with high levels of CXCL10 expression. On in situ hybridization, CXCL10+ cells colocalized with CD8+T cells in post-treatment prostatectomy tumor tissue. Neoadjuvant sipuleucel-T was also associated with upregulation of immune inhibitory checkpoints, including CTLA4 and TIGIT, and downregulation of the immune activation marker, dipeptidylpeptidase, DPP4. Treatment-associated declines in serum PSA were correlated with induction of Th1 response. In contrast, rises in serum PSA while on treatment were associated with the induction of multiple immune checkpoints, including CTLA4, CEACAM6 and TIGIT. This could represent adaptive immune resistance mechanisms induced by treatment. Taken together, neoadjuvant sipuleucel-T can induce both a Th1 response and negative immune regulation in the prostate cancer microenvironment.

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Section: Resultsmentioning

confidence: 99%

“…Genes previously shown to be characteristic of various immune cell populations were used to measure these populations’ abundance. 6 …”

Section: Methodsmentioning

confidence: 99%

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

et al. 2018

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“…In the attempt of defining the abundance and the functional profile of immune cell populations represented in liver tissue infiltrate, we took advantage of previous work identifying cell-specific gene expression profiles consistent with flow cytometry and immunohistochemical staining [14, 15]. …”

Section: Resultsmentioning

confidence: 99%

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

et al. 2018

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Background: The antitumor immune response may play a major role in the clinical outcome of hepatocellular carcinoma (HCC). We characterized the liver immune microenvironment by direct hybridization of RNA extracted from HCC and nontumorous tissues. Methods: RNA was extracted from frozen liver tissue samples of HCC (T; n = 30) and nontumorous tissues (NT; n = 33) obtained from 38 patients. Matched samples were available for 25 patients. The immune gene expression profile was analyzed with the nCounter GX Human Immunology v2 system (NanoString Technologies), which detects the expression levels of 579 immune response-related genes simultaneously. Results: Since the immune gene expression profile of T and NT tissues was significantly different, the prognostic relevance of the liver immune microenvironment was evaluated in the T and NT samples separately. Unsupervised clustering detected two main clusters of immune gene expression both in T and in NT liver samples. In both cases, the expression clusters identified groups of patients with a significantly different median time to HCC recurrence (TTR) but similar overall survival. Based on T tissue, two groups with median TTR of 19 and 127 months, respectively, were detected (p < 0.005). Expression of genes related to T-cell activation was associated with longer TTR. The analysis of NT tissue discriminated subsets of patients with median TTR of 22 and 68 months (p < 0.05). In contrast to T tissue, a predominant inflammatory immune environment was associated with shorter TTR. Conclusions: Immune gene expression profiles predictive of TTR could be identified both in HCC and in adjacent cirrhotic tissues. Longer TTR was associated with overexpression in T tissue and downregulation in NT tissue of the immune response and of inflammation-related genes.

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“…The NanoString nSolver 2.6 software was used for normalisation of expression counts using housekeeping genes following the manufacturer's recommendations . Data are displayed in expression count units of individual gene per patient compared with normal liver tissue, and internally normalised within each immune category (e.g.…”

Section: Methodsmentioning

confidence: 99%

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Figueiredo

Kalirai

Sacco

et al. 2020

The Journal of Pathology

109

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Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour‐infiltrating lymphocytes (TILs) within pUM and surrounding mUM – and some evidence of clinical responses to adoptive TIL transfer – strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour‐associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1, and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 − mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Gene expression markers of Tumor Infiltrating Leukocytes

Cited by 658 publications

References 32 publications

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

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