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

Ileana S. Mauldin, Nolan A. Wages, Anne M. Stowman, Ena Wang, Mark E. Smolkin, Walter C. Olson, Donna H. Deacon, Kelly T. Smith, Nadedja V. Galeassi, Kimberly A. Chianese‐Bullock, Lynn T. Dengel, Francesco M. Marincola, Gina R. Petroni, David W. Mullins, Craig L. Slingluff

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Introduction: 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. Patients and methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ 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 IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion: 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 IFNγ 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.

Original languageEnglish
Pages (from-to)1189-1199
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume65
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Fingerprint

C Chemokines
Interferon-gamma
Melanoma
Neoplasm Metastasis
T-Lymphocytes
Chemokine CXCL11
Neoplasms
Chemokine CXCL10
Vaccination
Vaccines
Chemokines
Chemokine CXCL9
Biopsy
Enzyme-Linked Immunospot Assay
Chemokine CCL5
Tumor Microenvironment

Keywords

  • Human
  • Immunotherapy
  • Interferon-gamma
  • Melanoma
  • T lymphocytes
  • Tumor vaccines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases. / Mauldin, Ileana S.; Wages, Nolan A.; Stowman, Anne M.; Wang, Ena; Smolkin, Mark E.; Olson, Walter C.; Deacon, Donna H.; Smith, Kelly T.; Galeassi, Nadedja V.; Chianese‐Bullock, Kimberly A.; Dengel, Lynn T.; Marincola, Francesco M.; Petroni, Gina R.; Mullins, David W.; Slingluff, Craig L.

In: Cancer Immunology, Immunotherapy, Vol. 65, No. 10, 01.10.2016, p. 1189-1199.

Research output: Contribution to journalArticle

Mauldin, IS, Wages, NA, Stowman, AM, Wang, E, Smolkin, ME, Olson, WC, Deacon, DH, Smith, KT, Galeassi, NV, Chianese‐Bullock, KA, Dengel, LT, Marincola, FM, Petroni, GR, Mullins, DW & Slingluff, CL 2016, 'Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases', Cancer Immunology, Immunotherapy, vol. 65, no. 10, pp. 1189-1199. https://doi.org/10.1007/s00262-016-1881-y
Mauldin, Ileana S. ; Wages, Nolan A. ; Stowman, Anne M. ; Wang, Ena ; Smolkin, Mark E. ; Olson, Walter C. ; Deacon, Donna H. ; Smith, Kelly T. ; Galeassi, Nadedja V. ; Chianese‐Bullock, Kimberly A. ; Dengel, Lynn T. ; Marincola, Francesco M. ; Petroni, Gina R. ; Mullins, David W. ; Slingluff, Craig L. / Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases. In: Cancer Immunology, Immunotherapy. 2016 ; Vol. 65, No. 10. pp. 1189-1199.
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abstract = "Introduction: 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. Patients and methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ 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 IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion: 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 IFNγ 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.",
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T1 - Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

AU - Mauldin, Ileana S.

AU - Wages, Nolan A.

AU - Stowman, Anne M.

AU - Wang, Ena

AU - Smolkin, Mark E.

AU - Olson, Walter C.

AU - Deacon, Donna H.

AU - Smith, Kelly T.

AU - Galeassi, Nadedja V.

AU - Chianese‐Bullock, Kimberly A.

AU - Dengel, Lynn T.

AU - Marincola, Francesco M.

AU - Petroni, Gina R.

AU - Mullins, David W.

AU - Slingluff, Craig L.

PY - 2016/10/1

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N2 - Introduction: 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. Patients and methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ 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 IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion: 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 IFNγ 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.

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