T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.
Istituto Oncologico Veneto, IOV-IRCCS, 35128 Padova, Italy. Electronic address: ilaria.marigo@ioveneto.it.
Ilaria
I
Marigo
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Serena
S
Zilio
Istituto Oncologico Veneto, IOV-IRCCS, 35128 Padova, Italy.
Giacomo
G
Desantis
INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris 75006, France; Université Paris Descartes, Paris 75006, France; Cordeliers Research Centre, Université Pierre et Marie Curie Paris 6, Paris 75006, France.
Bernhard
B
Mlecnik
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Andrielly H R
AHR
Agnellini
Department of Medicine, Verona University Hospital, 37134 Verona, Italy.
Stefano
S
Ugel
Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Maria Stella
MS
Sasso
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Joseph E
JE
Qualls
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Franz
F
Kratochvill
Istituto Oncologico Veneto, IOV-IRCCS, 35128 Padova, Italy; Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Paola
P
Zanovello
Istituto Oncologico Veneto, IOV-IRCCS, 35128 Padova, Italy.
Barbara
B
Molon
Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Carola H
CH
Ries
Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Valeria
V
Runza
Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Sabine
S
Hoves
INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris 75006, France; Université Paris Descartes, Paris 75006, France; Cordeliers Research Centre, Université Pierre et Marie Curie Paris 6, Paris 75006, France.
Amélie M
AM
Bilocq
INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris 75006, France; Université Paris Descartes, Paris 75006, France; Cordeliers Research Centre, Université Pierre et Marie Curie Paris 6, Paris 75006, France.
Gabriela
G
Bindea
Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, 41100 Modena, Italy.
Emilia M C
EMC
Mazza
Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, 41100 Modena, Italy.
Silvio
S
Bicciato
INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris 75006, France; Université Paris Descartes, Paris 75006, France; Cordeliers Research Centre, Université Pierre et Marie Curie Paris 6, Paris 75006, France.
Jérôme
J
Galon
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: peter.murray@stjude.org.
Peter J
PJ
Murray
Department of Medicine, Verona University Hospital, 37134 Verona, Italy. Electronic address: vincenzo.bronte@univr.it.
Vincenzo
V
Bronte
D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D001119:Arginase