Lapatinib and doxorubicin enhance the Stat1‐dependent antitumor immune response

Abstract

Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe reversal of immune tolerance represents one central goal in cancer immune therapies and serves as a rationale for developing [3,5]. Furthermore, these drugs can enhance the immunogenicity of the tumor epithelium, and as well change the immunosuppressive cytokine milieu produced by the tumor and its microenvironment, thereby facilitating the maturation and function of effector cells in innate and adaptive immunity [6]. The immunomodulatory effects of established anticancer drugs are also exploited to improve tumor vaccination protocols. An important animal model used in these studies is FVB/ N-MMTV-neu transgenic mice developing mammary cancer due to overexpression of neu, the normal rat homologue of HER2/erbB2 in the mammary gland [7]. These mice are immunotolerant to neu [8,9], but can be vaccinated with neu-directed vaccines to prevent tumor formation in combination with appropriate adjuvants such as GM-CSF, IL-12, and cyclophosphamide [10,11]. The IFN-induced transcription factor Stat1 has been described as important mediator of the antitumor response [12]. As a key regulator of innate as well as adaptive immunity, Stat1 is involved in immune surveillance [13] but has also been postulated to act as a tumor suppressor by tumor epithelium intrinsic mechanisms. As has been shown recently, Stat1-deficient mice spontaneously develop mammary tumors [14,15]. In MMTV-neu mammary tumor mice, deletion of Stat1 in the tumor epithelium as well as in the tumor stroma was shown to contribute to accelerated tumorigenesis [16,17]. The aim of the present study was to investigate this issue further in MMTV-neu mice as an animal model for erbB2-positive breast cancer, treated in vivo with two different types of drugs, the dual tyrosine kinase inhibitor lapatini which targets HER2/erbB2/neu and EGFR/erbB1, and the genotoxic anthracycline drug doxorubicin.Here, we show that in MMTV-neu mice the in vivo efficacy of lapatinib and/or doxorubicin treatment is dependent on CD8 . Both Stat1-deficient and -proficient mice developed mammary tumors with no significant differences in expression levels for erbB2 and in tumor histology ( Fig. 1A and Supporting Information Fig. 1).As described previously for other mouse models of erbB2-positive breast cancer [16,17], Stat1 deficiency resulted in a slight acceleration of the development of palpable tumors. Furthermore, we observed an increase in tumor multiplicity, with lowered levels of caspase 3 cleavage in the tumor and a slight increase of the fraction of proliferating cells in the tumor (Supporting Information Fig. 1). To assess the role of Stat1 in the response to chemotherapy, mice were treated with the erbB1/erbB2 targeting drug lapatinib and/or the genotoxic agent doxorubicin as soon as tumors were palpable. The response to therapy was monitored for 6 weeks. Treatment of Stat1-proficient mice either with lapatinib alone, doxorubicin or drug combination resu...

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…Considering the implications in cancer treatment, Stat1's response to chemotherapeutic drugs is likely to be controlled by both cell-autonomous and immune regulatory mechanisms. This notion is supported by a recent study showing that efficient treatment of ErbB2/HER2 mouse mammary tumors with the RTK inhibitor lapatinib and doxorubicin requires the immune regulatory function of Stat1 (14). Nevertheless, Stat1's function in drug-sensitive cells may be different from its function in drug-resistant tumor cells.…”

“…One mechanism depends on the induction of antitumor immune responses (6) and the other on the suppression of oncogenic signaling in a cell-autonomous (tumor cell-specific) manner (7)(8)(9)(10)(11). The antitumor properties of Stat1 have been best documented in breast cancers in which Stat1 assumes both immune regulatory and cell-autonomous functions to suppress either ErbB2/HER2 or estrogen receptor α (ERα)-mediated tumorigenesis (4,(10)(11)(12)(13)(14). Stat1 can also act as a promoter of mouse leukemogenesis caused by the activation of either Abelson murine leukemia viral oncogene homolog v-Abl or translocation-Ets-leukemia locus (TEL) and Janus kinase 2 fusion protein through immune regulatory mechanisms independent of IFN-γ (15).…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Conversely, CD4 + T cell depletion further delays MMTV-Neu tumor growth in mice treated with doxorubicin and lapatinib -a small molecule inhibitor of EGFR and ERBB2 [71]. The importance of CD4 + cells following paclitaxel or doxorubicin, without the addition of IDO inhibtors or lapatinib, remains to be established in mammary tumor-bearing MMTV-Neu mice, since these controls were not included in either study [70,71].…”

“…The importance of CD4 + cells following paclitaxel or doxorubicin, without the addition of IDO inhibtors or lapatinib, remains to be established in mammary tumor-bearing MMTV-Neu mice, since these controls were not included in either study [70,71]. Nonetheless, manipulation of Th17 cells or other CD4 + T cell subsets may be a useful strategy to combat cancer growth and metastasis when used in combination with chemotherapy.…”

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…Experiments in mouse cancer models have shown that STAT1 can function as a tumor suppressor via mechanisms that depend on the induction of antitumor immune responses as well as the inhibition of oncogenic signaling in a cell-autonomous (cell-specific) manner (8,9). The antitumor properties of STAT1 have been best characterized in mouse models of breast cancer, in which STAT1 assumes both immunoregulatory and cell-autonomous functions to suppress tumor formation by either ErbB2/HER2 or estrogen receptor a (8,10). Contrary to its antitumor effects in breast cancer, STAT1 promotes leukemogenesis in mice expressing v-ABL or TEL-JAK2 by increasing MHC class I expression and inhibiting tumor clearance by the immune system (11).…”