Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma

Abstract

BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.MethodsBALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.ResultsHER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75–80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.ConclusionsHER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.

Antipodoplanin antibody enhances the antitumor effects of CTLA‐4 blockade against malignant mesothelioma by natural killer cells

“…Ramamoorthi et al. elucidated that tumor‐killing effects of anti‐HER2 Ab required CD16 expression in the tumor microenvironment 34 . According to this evidence, we emphasized the ADCC activity in the antitumor effects and the localization of NK cells in tumor by treatment with anti‐PDPN Ab.…”

“…Recent reports revealed that Ab drugs targeting HER2 or epidermal growth factor receptor reinforced the antitumor effects of other immunotherapy and enhanced the accumulation of NK cells in tumor foci. 33,34 Cytotoxicity assays with mouse splenocytes revealed the ADCC and CDC activities of PMab-1-mG 2a against PDPN-expressing mesothelioma cells. However, monotherapy with PMab-1-mG 2a showed limited therapeutic effects in mesothelioma-bearing immunocompetent mice, while tumor-infiltrating NK cells were increased.…”

“…Natural killer cells, NKT cells and macrophages were reported to play the pivotal role in ADCC by expressing CD16. Recent reports revealed that Ab drugs targeting HER2 or epidermal growth factor receptor reinforced the antitumor effects of other immunotherapy and enhanced the accumulation of NK cells in tumor foci 33,34 . Ramamoorthi et al.…”

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

“…Conventional DC1 (cDC1) initially promotes CD4 + T cell activation and helps the priming and infiltration of CD8 + T cells into tumors [54]. Another study indicated that intertumoral delivery of DC combined with anti-HER2 therapy led to robust systemic antitumor immunity and complete regression in HER2-positive BC, as long as high levels of CD4+ and CD8+ T cells were present in the tumors [55].…”

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

“…HER2-DC1 comprises intratumoral multiepitope MHC class II HER2 peptide-pulsed type I polarized dendritic cells. Ramamoorthi G observed that HER2-DC1 combined with T-DM1 increased the levels of tumor-infiltrating CD4 and CD8 T, B, natural killer T, and NK cells in HER2 breast cancer-bearing mice and promoted complete tumor regression ( 35 ). ADCC effects of T-DM1 have been reported in other HER2-overexpressing cancers, such as lung and ovarian cancers.…”