PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity

Abstract

Trastuzumab is a humanized monoclonal antibody, and has been clinical employed to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, drug resistance to trastuzumab remains a challenge due to the generally uncharacterized interactive immune responses within the tumor tissue. In this study, by means of single-cell sequencing, we identified a novel podoplanin-positive (PDPN⁺) cancer-associated fibroblasts (CAFs) subset, which was enriched in trastuzumab resistant tumor tissues. Furthermore, we found that PDPN⁺ CAFs promote resistance to trastuzumab in HER2⁺ breast cancer by secreting immunosuppressive factors indoleamine 2,3-dioxygenase 1 (IDO1) as well as tryptophan 2,3-dioxygenase 2 (TDO2), thereby suppressing antibody-dependent cell-mediated cytotoxicity (ADCC), which was mediated by functional NK cells. A dual inhibitor IDO/TDO-IN-3 simultaneously targeting IDO1 and TDO2 showed a promising effect on reversing PDPN⁺ CAFs-induced suppression of NK cells mediated ADCC. Collectively, a novel subset of PDPN⁺ CAFs was identified in this study, which induced trastuzumab resistance in breast cancer of HER2⁺ status via inhibiting ADCC immune response mediated by NK cells, hinting that PDPN⁺ CAFs could be a novel target of treatment to increase the sensitivity of HER2⁺ breast cancer to trastuzumab.

Keywords: Breast cancer; Drug resistance; Immune response; Treatment; Tumor microenvironment.