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 cancer patients, 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 co-injected 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.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…For example, tasquinimod binds to and inhibits signaling by S100A9, a molecule known to be important for accumulation and activation of MDSCs (126). In murine prostate tumor models, tasquinimod treatment led to decreased MDSC numbers and functions, and increased antitumor responses (137). This treatment was well tolerated, slowed tumor progression, and increased survival in phase II trials in castrate-resistant prostate cancer patients (119).…”

Paquinimod reduces skin fibrosis in tight skin 1 mice, an experimental model of systemic sclerosis

“…In the tumor, these cells appear as tumor-associated M2 macrophages or infiltrating monocytic/granulocytic cells. Recent studies with tasquinimod, another quinoline compound, showed that tasquinimod triggers a polarization of macrophages from a M2 to a M1 phenotype in the tumour microenvironment [34,35].…”

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

“…Tasquinimod, a novel antitumor agent has been reported to prolong the progression-free survival of human castration-resistant prostate cancer patients [182]. Tasquinimod enhanced the effectiveness of immunotherapy, inhibited the accumulation of Ly6C+ MDSCs and CD206+ M2-like TAMs via targeting S100A9, furthermore CD11b+ myeloid cells showed less ArgI and iNOS expression which resulted in significantly reduced tumor growth in murine models of prostate cancer and melanoma [183] (Table 3). …”