Dataset Information

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

ABSTRACT: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFN? will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFN? intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFN? ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.Vaccination and intratumoral administration of IFN? were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFN? increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFN? promoted immune cell infiltration or induced anti-tumor immune gene signatures.The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFN? induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

SUBMITTER: Mauldin IS

PROVIDER: S-EPMC5037033 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

Mauldin Ileana S IS Wages Nolan A NA Stowman Anne M AM Wang Ena E Smolkin Mark E ME Olson Walter C WC Deacon Donna H DH Smith Kelly T KT Galeassi Nadedja V NV Chianese-Bullock Kimberly A KA Dengel Lynn T LT Marincola Francesco M FM Petroni Gina R GR Mullins David W DW Slingluff Craig L CL

Cancer immunology, immunotherapy : CII 20160813 10

<h4>Introduction</h4>Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.<h4>Patients and methods</h4>Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted ...[more]

PMID: 27522581

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Project description:BackgroundTuberculosis screening in psoriasis patients is complex due to the immunological alterations associated with psoriasis, the presence of comorbidities, and the effect of immunosuppressive treatment. However, it is not established whether the results of screening tests are affected by these factors in psoriasis patients.ObjectivesTo determine whether there is a change in the results of the tuberculin skin test (TST) or the interferon-gamma release assay (IGRA) in psoriasis patients living in tuberculosis (TB)-endemic area after 12 weeks of methotrexate (MTX) treatment and to investigate the association of the test results with clinical and inflammatory markers.MethodsForty-five patients were selected for a prospective single-arm self-controlled study and followed for at least 18 months. The TST, IGRA, Psoriasis Area and Severity Index (PASI), and inflammatory factors (erythrocyte sedimentation rate (ESR), C-reactive protein, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha levels), were determined before and after 12 weeks of oral 15 mg per week MTX administration and compared. The associations between the IGRA and TST results were verified before and after treatment according to inflammatory factors and clinical characteristics (age, blood glucose, weight, body mass index, disease duration, and PASI).ResultsWe collected data on 25 patients who completed the full course of therapy and the follow-up. None of the patients developed TB. TST positivity was significantly elevated at week 12 (25% baseline vs 44% at week 12, P < 0.037). Three IGRAs followed the TST conversions. There was no difference between TST and IGRA pre- or posttreatment. Serum IFN-γ increased significantly in week 12 (15.95 pg/ml baseline vs 18.82 pg/ml at week 12, P < 0.005) and tended to be higher among TST-positive patients (P = 0.072). The baseline IGRA was associated with a higher ESR (P = 0.038). None of the test results were associated with clinical characteristics.ConclusionsIn addition to the classic booster effect, TST conversions in patients using MTX can occur due to an increase in IFN-γ. However, it is not possible to exclude true TST conversions. Therefore, other diagnostic methods, like IGRA or chest tomography, should be used when the TST has intermediate results.

Dataset Information

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

Publications

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.

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