Abstract
BackgroundCyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.MethodsTo elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.ResultsGlobal transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) − which results in a strong but transient natural killer cell response followed by early tumor growth rebound − induced fewer cytokines and increased expression of drug metabolism genes.ConclusionsThese findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2597-2) contains supplementary material, which is available to authorized users.
Highlights
Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d)
The profile of gene expression changes seen in GL261 gliomas, which show strong immune responsiveness to CPA/6d treatment, is compared to the changes seen in two other C57BL/6 mouse strain (B6) mouse syngeneic tumor models that are intrinsically sensitive to CPA cytotoxicity, LLC Lewis lung carcinoma and B16F10 melanoma, but which, we show here, do not undergo CPA-induced tumor regression or mount a strong antitumor immune response
When assessing the uniqueness of the stringent upstream regulator (UPR) identified in the GL261(B6) tumor model (Additional file 4: Table S3A) as compared to the GL261(scid) model, we considered the full set of UPRs derived from CPA/6d-treated GL261(scid) tumors (Additional file 3: Table S2D; see Additional file 2: Figure S2)
Summary
Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). Certain cytotoxic anti-cancer drugs, including doxorubicin, oxaliplatin, and cyclophosphamide (CPA), can activate immunogenic tumor cell death, triggering robust antitumor immune responses [1, 2]. Tumorassociated gene responses identified in these xenograft models include induction of many cytokines, chemokines, and immune regulatory genes linked to innate immune cell recruitment and tumor regression, as well as tumor escape [21] It is unclear, which pathways and mechanisms dominate the response to CPA/6d treatment in an immune competent mouse host. Unknown is whether strong anti-tumor immune responses are activated by the CPA/6d regimen in other, non-glioma models that show strong intrinsic sensitivity to CPA cytotoxicity
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