TNBC, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is notoriously challenging to treat due to its aggressive nature and limited targeted therapy options. However, this new study, conducted by a team of scientists from [institution(s)], has uncovered a promising avenue for immunotherapy in TNBC patients.

The research team focused on the overexpression of NCL, a protein found at high levels in TNBC cells. They discovered that NCL-positive TNBC cells exhibited worse clinical outcomes when combined with high levels of PD-L1 expression, which dampens the immune response against cancer cells. This prompted the scientists to investigate ways to sensitize the immune system against NCL-positive TNBC cells.

To achieve this, the researchers employed a two-pronged approach. First, they utilized self-differentiated myeloid-derived antigen-presenting cells reactive against NCL, or SmartDCs-NCL, which were engineered to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). These SmartDCs-NCL activated NCL-specific T cells, which play a crucial role in immune response.

Additionally, the researchers combined the SmartDCs-NCL with recombinant human ribosomal protein substrate 3 (RPS3), which successfully induced maturation and activation of dendritic cells. This activation was characterized by the reduction of CD14 expression and the induction of CD11c, CD40, CD80, CD83, CD86, and HLA-DR, markers associated with immune cell activation.

Most notably, the combination of SmartDCs-NCL, RPS3, and an anti-PD-L1 peptide demonstrated significant killing activity of NCL-specific T cells against NCLHigh/PD-L1High TNBC cells. This killing activity was observed both in two-dimensional (2-D) and three-dimensional (3-D) culture systems, at specific effector:target ratios. Importantly, no killing effect was observed in normal mammary cells.

The researchers further investigated the mechanism behind the NCL-specific T-cell-mediated killing of TNBC cells. They discovered that the process involved both apoptotic and autophagic pathways. Notably, the induction of autophagy by curcumin, a natural autophagic stimulator, not only inhibited the expression of PD-L1 but also enhanced the cytolytic activity of NCL-specific T cells.

These groundbreaking findings offer exciting potential for the development of clinical approaches targeting NCLHigh/PD-L1High TNBC cells. The combination of NCL-specific T cells, a PD-L1 inhibitor, and an autophagic stimulator holds promise for improved treatment outcomes in patients with TNBC.