Abstract
The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2+ breast cancer patients. The tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu+ tumour cell line (TUBO) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of T cells were examined in both mouse strains. The outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of T cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional T cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.
Highlights
The use of Trastuzumab (Herceptin), a monoclonal antibody targeting HER2/neu, results in an increased median survival in Her2+ breast cancer patients
Our observation that rat-neu expressing TUBO tumours are highly immunogenic in WT BALB/c mice is in agreement with the finding of Reilly et al.[26] who demonstrated that the minimum tumour cell dose required for tumour outgrowth in 100% of the transplanted animals was 100-fold lower for the neu transgenic mice compared with non-transgenic mice
Our study confirms previous studies showing that CD4+ and CD8+ T cells can contribute to anti-neu monoclonal antibody (mAb) monotherapy to suppress the growth of the TUBO tumour in WT BALB/c immunocompetent mice[8,14]
Summary
The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2+ breast cancer patients. Several preclinical studies have suggested that innate www.nature.com/scientificreports immune responses are essential to anti-Her2/neu mAb cancer therapies through the recruitment of Fcγ receptor (FcγR) expressing immune cells which can mediate antibody-dependent cellular cytotoxicity (ADCC)[6,7,8] This is supported by the observation that in patients the efficacy of Trastuzumab correlates positively with the presence of allelic variants of FcγRIII with higher affinity for IgG9,10. Using such a transplantable tumor cell line, called TUBO, and WT BALB/c and F1 BALB/c FVB/N-Tg (MMTV-neu) mice as a recipient, findings of Park[8] and Mortenson[14] et al suggest that adaptive immunity, in particular the role of CD4+ and CD8+ T cells, is essential for the anti-neu mAb-mediated tumour regression We explored whether and to what extent both CD8+ and CD4+ T cells are involved in the therapeutic effects of anti-neu mAb in both WT BALB/c and BALB/c-NeuT tumor bearing mice
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