Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

• Published in: Scientific reports Vol. 10; no. 1; p. 3933
• Main Authors: Sow, Heng Sheng, Benonisson, Hreinn, Brouwers, Conny, Linssen, Margot M., Camps, Marcel, Breukel, Cor, Claassens, Jill, van Hall, Thorbald, Ossendorp, Ferry, Fransen, Marieke F., Verbeek, J. Sjef
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2020; Nature Publishing Group
• Subjects: 13/1; 13/31; 631/250/251; 631/67/1347; 64/110; 64/60; Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - therapeutic use; Breast cancer; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; ErbB-2 protein; Female; Flow Cytometry; Humanities and Social Sciences; Immunogenicity; Lapatinib - therapeutic use; Leukocyte Common Antigens - metabolism; Lymphocytes; Lymphocytes T; Male; Mammary Neoplasms, Animal - drug therapy; Mammary Neoplasms, Animal - immunology; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - immunology; Mice; Mice, Inbred BALB C; Monoclonal antibodies; multidisciplinary; Quinolines - therapeutic use; Rats; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Rodents; Science; Science (multidisciplinary); Signal Transduction; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Targeted cancer therapy; Trastuzumab; Trastuzumab - therapeutic use; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-60893-8

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.