Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity

Suneesh Kaimala, Yassir A. Mohamed, Nancy Nader, Jincy Issac, Eyad Elkord, Salem Chouaib, Maria J. Fernandez-Cabezudo, Basel K. Al-Ramadi

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b +Gr-1+ myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b+ cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

Original languageEnglish
Pages (from-to)587-599
Number of pages13
JournalCancer Immunology, Immunotherapy
Volume63
Issue number6
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Myeloid Cells
Salmonella
Phenotype
Neoplasms
Arginase
Interleukin-4
Spleen
Therapeutics
Adaptive Immunity
Growth
Immunotherapy
Vascular Endothelial Growth Factor A
Melanoma
Gene Expression
Proteins

Keywords

  • Macrophages
  • Myeloid suppressor cells
  • Salmonella
  • Tumor immunity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity. / Kaimala, Suneesh; Mohamed, Yassir A.; Nader, Nancy; Issac, Jincy; Elkord, Eyad; Chouaib, Salem; Fernandez-Cabezudo, Maria J.; Al-Ramadi, Basel K.

In: Cancer Immunology, Immunotherapy, Vol. 63, No. 6, 2014, p. 587-599.

Research output: Contribution to journalArticle

Kaimala, Suneesh ; Mohamed, Yassir A. ; Nader, Nancy ; Issac, Jincy ; Elkord, Eyad ; Chouaib, Salem ; Fernandez-Cabezudo, Maria J. ; Al-Ramadi, Basel K. / Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity. In: Cancer Immunology, Immunotherapy. 2014 ; Vol. 63, No. 6. pp. 587-599.
@article{c8b03f8bdf3a4de9b4290ca2889d3202,
title = "Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity",
abstract = "The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b +Gr-1+ myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b+ cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.",
keywords = "Macrophages, Myeloid suppressor cells, Salmonella, Tumor immunity",
author = "Suneesh Kaimala and Mohamed, {Yassir A.} and Nancy Nader and Jincy Issac and Eyad Elkord and Salem Chouaib and Fernandez-Cabezudo, {Maria J.} and Al-Ramadi, {Basel K.}",
year = "2014",
doi = "10.1007/s00262-014-1543-x",
language = "English",
volume = "63",
pages = "587--599",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "6",

}

TY - JOUR

T1 - Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity

AU - Kaimala, Suneesh

AU - Mohamed, Yassir A.

AU - Nader, Nancy

AU - Issac, Jincy

AU - Elkord, Eyad

AU - Chouaib, Salem

AU - Fernandez-Cabezudo, Maria J.

AU - Al-Ramadi, Basel K.

PY - 2014

Y1 - 2014

N2 - The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b +Gr-1+ myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b+ cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

AB - The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b +Gr-1+ myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b+ cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

KW - Macrophages

KW - Myeloid suppressor cells

KW - Salmonella

KW - Tumor immunity

UR - http://www.scopus.com/inward/record.url?scp=84901635201&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901635201&partnerID=8YFLogxK

U2 - 10.1007/s00262-014-1543-x

DO - 10.1007/s00262-014-1543-x

M3 - Article

VL - 63

SP - 587

EP - 599

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 6

ER -