Fig. 9
From: Nanotechnology approaches to addressing HER2-positive breast cancer
(Reprinted with permission from (Lu et al. 2018). Copyright 2018, American Chemical Society. Further permissions related to the material excerpted should be directed to the ACS)
Schematic to explain BC immunotherapy by combined delivery of an immunogenic cell death stimulus plus an inhibitor of the IDO-1 pathway. DOX delivery to the tumor site provides an effective stimulus for ICD, which is characterized by calreticulin (CRT) expression (an “eat-me” signal for dendritic cell uptake) on the cancer cell surface. Subsequent release of adjuvant stimuli, HMGB-1 and ATP, by the dying cancer cells induces DC maturation and tumor antigen presentation to naive T-cells. Recruitment of CD8+ cytotoxic T-lymphocytes triggers a full-fledged immune response, provided that the tumor infiltrating lymphocytes can escape the immunosuppressive micromilieu at the BC tumor site. These immunosuppressive pathways include a contribution by FOXP-3+ regulatory T-cells, autoregulatory effects of immune checkpoint receptors (e.g., PD-1), and the metabolic effects of the overexpressed IDO-1 immune surveillance pathway. The small molecule inhibitor IND interferes in the IDO-1 pathway. The improved pharmacokinetics of drug delivery by the nanocarrier allows achievement of sufficiently high tumor drug levels to trigger an effective and sustained immune response for the reduction or elimination of the primary BC tumor and its metastases