Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models

Li Shen, Anette Sundstedt, Michael Ciesielski, Kiersten Marie Miles, Mona Celander, Remi Adelaiye, Ashley Orillion, Eric Ciamporcero, Swathi Ramakrishnan, Leigh Ellis, Robert Fenstermaker, Scott I. Abrams, Helena Eriksson, Tomas Leanderson, Anders Olsson, Roberto Pili

Research output: Contribution to journalArticle

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Abstract

A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumorspecific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNg production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies.

Original languageEnglish (US)
Pages (from-to)136-148
Number of pages13
JournalCancer immunology research
Volume3
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

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Myeloid Cells
Immunotherapy
Neoplasms
Immunosuppressive Agents
Prostatic Neoplasms
Calgranulin B
tasquinimod
T-Lymphocytes
Arginase
Superantigens
Cancer Vaccines
Tumor Microenvironment
Castration
Nitric Oxide Synthase Type II
Antineoplastic Agents
Population
Melanoma
Macrophages
Neoplasm Metastasis
Phenotype

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. / Shen, Li; Sundstedt, Anette; Ciesielski, Michael; Miles, Kiersten Marie; Celander, Mona; Adelaiye, Remi; Orillion, Ashley; Ciamporcero, Eric; Ramakrishnan, Swathi; Ellis, Leigh; Fenstermaker, Robert; Abrams, Scott I.; Eriksson, Helena; Leanderson, Tomas; Olsson, Anders; Pili, Roberto.

In: Cancer immunology research, Vol. 3, No. 2, 01.02.2015, p. 136-148.

Research output: Contribution to journalArticle

Shen, L, Sundstedt, A, Ciesielski, M, Miles, KM, Celander, M, Adelaiye, R, Orillion, A, Ciamporcero, E, Ramakrishnan, S, Ellis, L, Fenstermaker, R, Abrams, SI, Eriksson, H, Leanderson, T, Olsson, A & Pili, R 2015, 'Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models', Cancer immunology research, vol. 3, no. 2, pp. 136-148. https://doi.org/10.1158/2326-6066.CIR-14-0036
Shen, Li ; Sundstedt, Anette ; Ciesielski, Michael ; Miles, Kiersten Marie ; Celander, Mona ; Adelaiye, Remi ; Orillion, Ashley ; Ciamporcero, Eric ; Ramakrishnan, Swathi ; Ellis, Leigh ; Fenstermaker, Robert ; Abrams, Scott I. ; Eriksson, Helena ; Leanderson, Tomas ; Olsson, Anders ; Pili, Roberto. / Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. In: Cancer immunology research. 2015 ; Vol. 3, No. 2. pp. 136-148.
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AU - Adelaiye, Remi

AU - Orillion, Ashley

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AU - Ramakrishnan, Swathi

AU - Ellis, Leigh

AU - Fenstermaker, Robert

AU - Abrams, Scott I.

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AU - Leanderson, Tomas

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