Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo

Abstract

Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.

Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy

“…Although they observed that cyclophosphamide therapy resulted in the preferential deletion of Treg cells, similar to previous studies, this therapy also enhanced the production of chronic inflammatory mediators by melanoma cells associated with an accumulation of Gr1+CD11b+ MDSCs. However, in a similar study of murine colon cancer, the ability of low-dose cyclophosphamide to promote MDSC expansion was reversed when low-dose gemcitabine was concurrently administered, resulting in reduced levels of MDSCs and potent antitumor immune responses [52]. This is consistent with a study by Suzuki et al demonstrating that gemcitabine (a single dose of 120 mg/kg) can selectively eliminate Gr1+CD11b+MDSCs in tumor-bearing mice [53].…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…85 Other reports, however, show that CTX induces early myeloid effector cells that may inhibit tumor cell growth through nitric oxide (NO) release, 86 and that metronomic CTX plus gemcitabine mitigates Treg-and MDSC-mediated immunosuppression and elicits antitumor immunity in vivo. 87 Among taxanes, paclitaxel specifically impairs viability and cytokine production in FOXP3 þ Treg cells, but not in FOXP3 À CD4 effector cells. 88 Docetaxel, another antimicrotubule agent, was shown to polarize MDSCs toward an M1-like phenotype, and to selectively kill MDSCs while sparing the M1-like cells.…”

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

“…As discussed below, this is consistent with the different locus of activity of each of these agents. Cyclophosphamide has been shown to mitigate Treg-mediated immunosuppression in rodents and in patients with cancer (34), as well as to promote immunogenic cell death and T cellmediated immunity (40). To determine combination effects with anti-SEMA4D, a suboptimal dose of cyclophosphamide was administered 1 day before immunotherapy.…”