Abstract
PurposeWe have compared cure from local/metastatic tumor growth in BALB/c mice receiving EMT6 or the poorly immunogenic, highly metastatic 4THM, breast cancer cells following manipulation of immunosuppressive CD200:CD200R interactions or conventional chemotherapy.MethodsWe reported previously that EMT6 tumors are cured in CD200R1KO mice following surgical resection and immunization with irradiated EMT6 cells and CpG oligodeoxynucleotide (CpG), while wild-type (WT) animals developed pulmonary and liver metastases within 30 days of surgery. We report growth and metastasis of both EMT6 and a highly metastatic 4THM tumor in WT mice receiving iv infusions of Fab anti-CD200R1 along with CpG/tumor cell immunization. Metastasis was followed both macroscopically (lung/liver nodules) and microscopically by cloning tumor cells at limiting dilution in vitro from draining lymph nodes (DLN) harvested at surgery. We compared these results with local/metastatic tumor growth in mice receiving 4 courses of combination treatment with anti-VEGF and paclitaxel.ResultsIn WT mice receiving Fab anti-CD200R, no tumor cells are detectable following immunotherapy, and CD4+ cells produced increased TNFα/IL-2/IFNγ on stimulation with EMT6 in vitro. No long-term cure was seen following surgery/immunotherapy of 4THM, with both microscopic (tumors in DLN at limiting dilution) and macroscopic metastases present within 14 d of surgery. Chemotherapy attenuated growth/metastases in 4THM tumor-bearers and produced a decline in lung/liver metastases, with no detectable DLN metastases in EMT6 tumor-bearing mice-these latter mice nevertheless showed no significantly increased cytokine production after restimulation with EMT6 in vitro. EMT6 mice receiving immunotherapy were resistant to subsequent re-challenge with EMT6 tumor cells, but not those receiving curative chemotherapy. Anti-CD4 treatment caused tumor recurrence after immunotherapy, but produced no apparent effect in either EMT6 or 4THM tumor bearers after chemotherapy treatment.ConclusionImmunotherapy, but not chemotherapy, enhances CD4+ immunity and affords long-term control of breast cancer growth and resistance to new tumor foci.
Highlights
The immunoregulatory molecule CD200 has been reported to regulate growth of human solid tumors [1,2] and hematological tumors [3,4,5]
Surgical resection followed by immunization along with Fab anti-CD200R, or chemotherapy alone, prevents metastasis of EMT6, but not 4THM, in BALB/c mice
Surgical resection of a primary tumor in CD200R1KO mice followed by immunization prevented macroscopic lung/liver metastases enumerated at 90 d post tumor inoculation, compared with surgery alone [9]
Summary
The immunoregulatory molecule CD200 has been reported to regulate growth of human solid tumors [1,2] and hematological tumors [3,4,5]. In contrast to these observations, growth of the highly metastatic 4THM breast tumor (derived from a 4T1 parent line) was increased in CD200R1KO mice, with somewhat diminished growth in CD200tg animals [8].Surgical resection in CD200R1KO EMT6 tumor-bearing mice, followed by immunization with CpG as adjuvant, cured CD200R1KO mice of breast cancer recurrence in the absence of lung/liver metastases, and of micro metastases (defined by limiting dilution cloning in vitro) in DLN [9] Multiple factors both intrinsic to tumor cells themselves and host associated elements are implicated in tumor metastasis [10,11,12,13,14]. CD200R1KO mice showed increased growth of 4THM tumors [24]
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