PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer

Abstract

Abstract. Placenta-specific 1 (PLAC1), a novel cancer-testis antigen (CTA), is expressed in a number of different human malignancies. It is frequently produced in breast cancer, serving a function in tumorigenesis. Adoptive immunotherapy using T cell receptor (TCR)-engineered T cells against CTA mediates objective tumor regression; however, to the best of our knowledge, targeting PLAC1 using engineered T cells has not yet been attempted. In the present study, the cDNAs encoding TCRα-and β-chains specific for human leukocyte antigen (HLA)-A * 0201-restricted PLAC1 were cloned from a cytotoxic T-lymphocyte, generated by in vitro by the stimulation of CD8+ T cells using autologous HLA-A2+ dendritic cells loaded with a PLAC1-specific peptide (p28-36, VLCSIDWFM). The TCRα/β-chains were linked by a 2A peptide linker (TCRα-Thosea asigna virus-TCRβ), and the constructs were cloned into the lentiviral vector, followed by transduction into human cytotoxic (CD8+) T cells. The efficiency of transduction was up to 25.16%, as detected by PLAC1 multimers. TCR-transduced CD8+ T cells, co-cultured with human non-metastatic breast cancer MCF-7 cells (PLAC1+, HLA-A2+) and triple-negative breast cancer MDAMB-231 cells (PLAC1+, HLA-A2+), produced interferon γ and tumor necrosis factor α, suggesting TCR activation. Furthermore, the PLAC1 TCR-transduced CD8+ T cells efficiently and specifically identified and annihilated the HLA-A2+/PLAC1+ breast cancer cell lines in a lactate dehydrogenase activity assay. Western blot analysis demonstrated that TCR transduction stimulated the production of mitogen-activated protein kinase signaling molecules, extracellular signal-regulated kinases 1/2 and nuclear factor-κB, through phosphoinositide 3-kinase γ-mediated phosphorylation of protein kinase B in CD8+ T cells. Xenograft mouse assays revealed that PLAC1 TCR-transduced CD8+T cells significantly delayed the tumor progression in mice-bearing breast cancer compared with normal saline or negative control-transduced groups. In conclusion, a novel HLA-A2-restricted and PLAC1-specific TCR was identified. The present study demonstrated PLAC1 to be a potential target for breast cancer treatment; and the usage of PLAC1-specific TCR-engineered T cells may be a novel strategy for PLAC1-positive breast cancer treatment.

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers

“…This search uncovered placenta-specific 1 (PLAC1), initially identified as a target of autologous humoral immunity in gastric cancer and hepatocellular carcinoma patients, and the first CPA reported to represent a class of TAAs distinct from CTAs and oncofetal antigens 56 , 57 . A TCR recognizing an HLA-A*0201-restricted peptide derived from PLAC1 was recently isolated and shown to possess antitumor activity against human breast cancer cells in pre-clinical models, but have not yet been tested in clinical trials 58 . As shown in Fig.…”

Adoptive Cell Therapy in Breast Cancer: A Current Perspective of Next-Generation Medicine

“…Mounting clinical evidence on several tumor types along with preclinical data on BC underscores the rationale for TCR use in BC patients (34)(35)(36)(37). Of note, in both hormone-dependent and independent BC cell lines and in xenograft mice, Li et al reported a notable enhancement of anti-tumor cytotoxicity by CD8 + T cells transduced with an MHC-A2-restricted placenta-specific 1 (PLAC1)-TCR molecule (38). However, to the best of our knowledge, evidence on humans is still lacking, with many ongoing clinical trials testing intravenous infusions of TCR-engineered T cells against TAs such as HER2, NYESO-1, and MAGE-A3 ( Table 1).…”

Immunotherapeutic interventions of Triple Negative Breast Cancer

“…The large amount of attention has recently led to the increased development of this ACT, which has shown encouraging outcomes in studies of TCR-engineered T cells directed against NY-ESO-1, MAGE and GP100, with significant clinical successes in patients with colorectal carcinoma, synovial sarcoma, metastatic melanoma and multiple myeloma [ 126 , 127 ]. Recently, placenta-specific 1 (PLAC1)-specific HLA-A0201-restricted TCR-engineered CD8 + T cells were developed to kill breast cancer cells by producing IFN-γ and TNF-α [ 128 ]. However, more widespread utilization of TCR-engineered T cells in solid tumours such as TNBC calls for the enhancement of long-term survival and function of the cells, as well as closed culture procedures capable of expanding T cells to sufficient numbers for clinical application.…”