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Identification of HLA class II-restricted T cell receptors against shared PIK3CA mutations in patients with
S M Rafiqul Islam1, Samantha Seitter1, Maria Parkhurst1
1National Cancer Institute, Surgery Branch, National Institutes of Health, Bethesda, MD, USA.
Abstract:
PIK3CA is the third most common mutated gene in epithelial cancers, behind only TP53 and KRAS. Somatic PIK3CA mutations occur predominantly in the protein's hotspot locations H1047, E545, E542 and N345, and evidence of those alterations eliciting immune responses has been limited. HLA class I-restricted TCRs against E545K and H1047L have, only recently, been identified following in vitro sensitization (IVS) with peripheral blood lymphocytes (PBL) from normal donors. In this study, we examined the immunogenicity of PIK3CA in patients with epithelial cancers of diverse histology, by testing TIL and antigen-experienced PBL against autologous hotspot PIK3CA mutations. Two distinct TCRs specific to PIK3CAN345K, restricted by HLA-class II pair DPB1*04:01/DPA1*01:03, were identified in a patient with colon cancer, following independently a TIL screen and an IVS of memory CD4 + T cells from the peripheral blood. Patient PBL engineered to express each TCR suppressed the in vitro growth of two cell lines modified to express the DPB1*04:01/DPA1*01:03 pair and full length PIK3CAN345K protein. A TCR specific to the PIK3CAE545K, restricted by HLA-DRB1*04:01, was also identified following IVS of memory CD4 + PBL from another patient, with rectal cancer. Autologous PBL, gene engineered to express the PIK3CAE545K-specific TCR, suppressed the in vitro growth of two cancer cell lines, which endogenously expressed the PIK3CAE545K neoantigen. This study identified three PIK3CA-specific TCRs against two shared mutations, restricted by common HLA-class II molecules, using antigen-experienced TIL and memory PBL from patients with epithelial cancers and may further allow the development of off-the-shelf T cell immunotherapy strategies targeting PIK3CA.
Insights
Researchers identified three T cell receptors (TCRs) targeting common PIK3CA mutations in epithelial cancers. This discovery advances potential off-the-shelf T cell immunotherapies for PIK3CA-driven cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- PIK3CA mutations are frequent in epithelial cancers, but their immunogenicity is poorly understood.
- Previous studies identified limited T cell receptor (TCR) responses to specific PIK3CA mutations (E545K, H1047L).
Purpose of the Study:
- To investigate the immunogenicity of hotspot PIK3CA mutations in patients with epithelial cancers.
- To identify and characterize T cell responses against PIK3CA neoantigens.
Main Methods:
- Tumor-infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from cancer patients were tested against autologous PIK3CA mutations.
- In vitro sensitization (IVS) was used to identify antigen-experienced T cells.
- Gene engineering was employed to express identified TCRs in patient PBL for functional assays.
Main Results:
- Three PIK3CA-specific TCRs were identified: two targeting PIK3CAN345K (restricted by HLA-DPB1*04:01/DPA1*01:03) and one targeting PIK3CAE545K (restricted by HLA-DRB1*04:01).
- Engineered T cells expressing these TCRs suppressed the in vitro growth of cancer cell lines harboring the respective PIK3CA mutations.
- Responses were observed using both TIL and memory CD4+ T cells from patients with colon and rectal cancers.
Conclusions:
- This study demonstrates the immunogenicity of PIK3CA mutations in epithelial cancers.
- Identified PIK3CA-specific TCRs restricted by common HLA-class II molecules offer potential for developing targeted immunotherapies.
- These findings support the development of off-the-shelf T cell therapies for PIK3CA-mutated cancers.
