A CD40 Agonist and PD-1 Antagonist Antibody Reprogram the Microenvironment of Nonimmunogenic Tumors to Allow T-cell–Mediated Anticancer Activity

Hayley S. Ma, Bibhav Poudel, Evanthia Roussos Torres, John William Sidhom, Tara M. Robinson, Brian Christmas, Blake Scott, Kayla Cruz, Skylar Woolman, Valerie Z. Wall, Todd Armstrong, Elizabeth M. Jaffee

Research output: Contribution to journalArticle

Abstract

In cancers with tumor-infiltrating lymphocytes (TILs), monoclonal antibodies (mAbs) that block immune checkpoints such as CTLA-4 and PD-1/PD-L1 promote antitumor T-cell immunity. Unfortunately, most cancers fail to respond to single-agent immunotherapies. T regulatory cells, myeloid derived suppressor cells (MDSCs), and extensive stromal networks within the tumor microenvironment (TME) dampen antitumor immune responses by preventing T-cell infiltration and/or activation. Few studies have explored combinations of immune-checkpoint antibodies that target multiple suppressive cell populations within the TME, and fewer have studied the combinations of both agonist and antagonist mAbs on changes within the TME. Here, we test the hypothesis that combining a T-cell–inducing vaccine with both a PD-1 antagonist and CD40 agonist mAbs (triple therapy) will induce T-cell priming and TIL activation in mouse models of nonimmunogenic solid malignancies. In an orthotopic breast cancer model and both subcutaneous and metastatic pancreatic cancer mouse models, only triple therapy was able to eradicate most tumors. The survival benefit was accompanied by significant tumor infiltration of IFNg-, Granzyme B-, and TNFa-secreting effector T cells. Further characterization of immune populations was carried out by high-dimensional flow-cytometric clustering analysis and visualized by t-distributed stochastic neighbor embedding (t-SNE). Triple therapy also resulted in increased infiltration of dendritic cells, maturation of antigen-presenting cells, and a significant decrease in granulocytic MDSCs. These studies reveal that combination CD40 agonist and PD-1 antagonist mAbs reprogram immune resistant tumors in favor of antitumor immunity.

Original languageEnglish (US)
Pages (from-to)428-442
Number of pages15
JournalCancer Immunology Research
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2019

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Tumor Microenvironment
Antibodies
Monoclonal Antibodies
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Neoplasms
Immunity
Granzymes
Antigen-Presenting Cells
Regulatory T-Lymphocytes
Lymphocyte Activation
Pancreatic Neoplasms
Immunotherapy
Dendritic Cells
Population
Cluster Analysis
Therapeutics
Vaccines
Breast Neoplasms

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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A CD40 Agonist and PD-1 Antagonist Antibody Reprogram the Microenvironment of Nonimmunogenic Tumors to Allow T-cell–Mediated Anticancer Activity. / Ma, Hayley S.; Poudel, Bibhav; Torres, Evanthia Roussos; Sidhom, John William; Robinson, Tara M.; Christmas, Brian; Scott, Blake; Cruz, Kayla; Woolman, Skylar; Wall, Valerie Z.; Armstrong, Todd; Jaffee, Elizabeth M.

In: Cancer Immunology Research, Vol. 7, No. 3, 01.03.2019, p. 428-442.

Research output: Contribution to journalArticle

Ma, Hayley S. ; Poudel, Bibhav ; Torres, Evanthia Roussos ; Sidhom, John William ; Robinson, Tara M. ; Christmas, Brian ; Scott, Blake ; Cruz, Kayla ; Woolman, Skylar ; Wall, Valerie Z. ; Armstrong, Todd ; Jaffee, Elizabeth M. / A CD40 Agonist and PD-1 Antagonist Antibody Reprogram the Microenvironment of Nonimmunogenic Tumors to Allow T-cell–Mediated Anticancer Activity. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 3. pp. 428-442.
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