Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a phase 0 clinical trial

Shihong Zhang, Karan Kohli, R. Graeme Black, Lu Yao, Sydney M. Spadinger, Qianchuan He, Venu G. Pillarisetty, Lee D Cranmer, Brian A. Van Tine, Cassian Yee, Robert H. Pierce, Stanley R. Riddell, Robin L. Jones, Seth M. Pollack

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/ round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

Original languageEnglish (US)
Pages (from-to)1237-1243
Number of pages7
JournalCancer Immunology Research
Volume7
Issue number8
DOIs
StatePublished - Jan 1 2019

Fingerprint

Interferons
Synovial Sarcoma
Clinical Trials
Liposarcoma
T-Lymphocytes
Tumor Microenvironment
Neoplasms
Major Histocompatibility Complex
Immunotherapy
Antigens
Antigen Presentation
Neoplasm Antigens
Myeloid Cells
Therapeutics
Inflammation
Phenotype
Biopsy
Gene Expression

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors : Results of a phase 0 clinical trial. / Zhang, Shihong; Kohli, Karan; Graeme Black, R.; Yao, Lu; Spadinger, Sydney M.; He, Qianchuan; Pillarisetty, Venu G.; Cranmer, Lee D; Van Tine, Brian A.; Yee, Cassian; Pierce, Robert H.; Riddell, Stanley R.; Jones, Robin L.; Pollack, Seth M.

In: Cancer Immunology Research, Vol. 7, No. 8, 01.01.2019, p. 1237-1243.

Research output: Contribution to journalArticle

Zhang, S, Kohli, K, Graeme Black, R, Yao, L, Spadinger, SM, He, Q, Pillarisetty, VG, Cranmer, LD, Van Tine, BA, Yee, C, Pierce, RH, Riddell, SR, Jones, RL & Pollack, SM 2019, 'Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a phase 0 clinical trial', Cancer Immunology Research, vol. 7, no. 8, pp. 1237-1243. https://doi.org/10.1158/2326-6066.CIR-18-0940
Zhang, Shihong ; Kohli, Karan ; Graeme Black, R. ; Yao, Lu ; Spadinger, Sydney M. ; He, Qianchuan ; Pillarisetty, Venu G. ; Cranmer, Lee D ; Van Tine, Brian A. ; Yee, Cassian ; Pierce, Robert H. ; Riddell, Stanley R. ; Jones, Robin L. ; Pollack, Seth M. / Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors : Results of a phase 0 clinical trial. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 8. pp. 1237-1243.
@article{f5600c0b95704fcbad05efe9c583fcf3,
title = "Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a phase 0 clinical trial",
abstract = "Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/ round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into {"}hot{"} tumors will work in concert with anti–PD-1 therapy to provide patient benefit.",
author = "Shihong Zhang and Karan Kohli and {Graeme Black}, R. and Lu Yao and Spadinger, {Sydney M.} and Qianchuan He and Pillarisetty, {Venu G.} and Cranmer, {Lee D} and {Van Tine}, {Brian A.} and Cassian Yee and Pierce, {Robert H.} and Riddell, {Stanley R.} and Jones, {Robin L.} and Pollack, {Seth M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/2326-6066.CIR-18-0940",
language = "English (US)",
volume = "7",
pages = "1237--1243",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Systemic Interferon-g Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors

T2 - Results of a phase 0 clinical trial

AU - Zhang, Shihong

AU - Kohli, Karan

AU - Graeme Black, R.

AU - Yao, Lu

AU - Spadinger, Sydney M.

AU - He, Qianchuan

AU - Pillarisetty, Venu G.

AU - Cranmer, Lee D

AU - Van Tine, Brian A.

AU - Yee, Cassian

AU - Pierce, Robert H.

AU - Riddell, Stanley R.

AU - Jones, Robin L.

AU - Pollack, Seth M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/ round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

AB - Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/ round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

UR - http://www.scopus.com/inward/record.url?scp=85070489386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070489386&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-18-0940

DO - 10.1158/2326-6066.CIR-18-0940

M3 - Article

C2 - 31171504

AN - SCOPUS:85070489386

VL - 7

SP - 1237

EP - 1243

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 8

ER -