Neoepitope targets of tumour-infiltrating lymphocytes from patients with pancreatic cancer

Abstract

BackgroundPancreatic cancer exhibits a poor prognosis and often presents with metastasis at diagnosis. Immunotherapeutic approaches targeting private cancer mutations (neoantigens) are a clinically viable option to improve clinical outcomes.Methods3/40 TIL lines (PanTT26, PanTT39, PanTT77) were more closely examined for neoantigen recognition. Whole-exome sequencing was performed to identify non-synonymous somatic mutations. Mutant peptides were synthesised and assessed for antigen-specific IFN-γ production and specific tumour killing in a standard Cr51 assay. TIL phenotype was tested by flow cytometry. Lymphocytes and HLA molecules in tumour tissue were visualised by immunohistochemistry.ResultsPanTT26 and PanTT39 TILs recognised and killed the autologous tumour cells. PanTT26 TIL recognised the KRASG12v mutation, while a PanTT39 CD4+ TIL clone recognised the neoepitope (GLLRYWRTERLF) from an aquaporin 1-like protein (gene: K7N7A8). Repeated stimulation of TILs with the autologous tumour cells line lead to focused recognition of several mutated targets, based on IFN-γ production. TILs and corresponding PBMCs from PanTT77 showed shared as well as mutually exclusively tumour epitope recognition (TIL-responsive or PBMC-responsive).ConclusionThis study provides methods to robustly screen T-cell targets for pancreatic cancer. Pancreatic cancer is immunogenic and immunotherapeutic approaches can be used to develop improved, targeted therapies.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

“…Furthermore, the high stromal density and absence of angiogenesis dampen the infiltration of infused cells, and the suppressive TME also inactivates infiltrating cells. Promisingly, substantial progress has been made regarding PDAC TILs in recent years [135][136][137]. These results exploited potential tools to obtain multiple tumourspecific colonies and even a single TIL colony specific for endogenous tumour cells.…”

“…Importantly, they reported that peripheral blood mononuclear cells (PBMCs) as well as TILs could be used to screen neoantigens. These results pave the way for highly specific and personalized ACT [137] since targeting personalized mutations has been demonstrated to be a durable approach for the treatment of metastatic solid tumours with a relatively low mutation burden [138].…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Neoantigen-specific T cells can be identified in patients not only with melanoma, but also with epithelial cancers, such as lung cancer [119,120], gastrointestinal cancer [121][122][123], ovarian cancer [124][125][126], breast cancer [127] and pancreatic cancer [128]. Case reports have demonstrated that treatment of the gastrointestinal and breast cancer patients with a T cell population highly enriched in neoepitope-specific T cells caused tumour regression [121,123,127].…”

Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma

“…Many attempts have been made to find new antigens and use them for immunotherapy in various cancer types, 55 including PDAC. 55 Neoantigens, which have high tumor specificity, exhibit distinctive advantages when used in CAR-T therapy. In addition, tumors from different patients may express different neoantigens, and neoantigen-guided CAR-T therapy will conform better to the requirements of precision medicine.…”