title: Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models.
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. Tumor-specific CD8(+) T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ 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.
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Sundstedt
authors.affiliation: Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Ciesielski
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kiersten Marie
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Mona
authors.initials: M
authors.lastname: Celander
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Remi
authors.initials: R
authors.lastname: Adelaiye
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Ashley
authors.initials: A
authors.lastname: Orillion
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Eric
authors.initials: E
authors.lastname: Ciamporcero
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.affiliation: Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Fenstermaker
authors.affiliation: Department of Tumor Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.affiliation: Active Biotech AB, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Eriksson
authors.affiliation: Active Biotech AB, Lund, Sweden. Immunology Group, Lund University, Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.affiliation: Active Biotech AB, Lund, Sweden. Roberto.Pili@RoswellPark.org anders.olsson@activebiotech.com.
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Roberto.Pili@RoswellPark.org anders.olsson@activebiotech.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D002369:Castration; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007108:Immune Tolerance / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D011804:Quinolines / Q000627:therapeutic use*; D015363:Quinolones; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D011804:Quinolines; D015363:Quinolones; C516109:tasquinimod