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Identification of T cell receptors targeting a neoantigen derived from recurrently mutated FGFR3

Tate, Tomohiro 京都大学 DOI:10.14989/doctor.k24803

2023.05.23

概要

In addition to surgery, chemotherapy, and radiotherapy, immunotherapy now plays
a critical role in cancer management. Immune checkpoint inhibitors (ICIs), such as
antibodies against programmed death-1 (PD-1), PD-1 ligand (PD-L1), and cytotoxic T
lymphocyte-associated antigen 4 (CTLA-4), have considerably improved the prognosis
of patients with various types of cancer, especially in cancers with "inflamed" tumors
characterized by high immune cell infiltration, high PD-L1 expression, and high mutation
burden [1–3]. However, clinical responses to ICIs have been limited to only 10%–40% of
patients, and most patients experienced little or no clinical benefit. For patients not responding to ICIs due to low immune cell infiltration, a cancer vaccine or adoptive cell therapies
are promising approaches to increase or induce active cancer-reactive T cells. Neoantigens,
antigens derived from mutated proteins generated by somatic mutations in cancer cells,
are thought to be good targets for immunotherapies because of their high specificity to
tumor cells.
To facilitate neoantigen-targeting immunotherapies, we have established pipelines to
predict neoantigens from patients’ genome sequencing data to identify neoantigen-specific
T cells and T cell receptors (TCRs), and to generate neoantigen-specific TCR-engineered
T cells [4–8]. Because neoantigens are not often shared among multiple cancer patients,
the personalized selection of appropriate target neoantigens for individual patients is
required. Recently, several reports demonstrated that "shared neoantigens", referring to
mutated antigens commonly detected in a subset of cancer patients, were targeted by
tumor-infiltrating T lymphocytes (TILs) [9–11]. Therefore, shared neoantigens could be
broadly applicable targets for immunotherapies in different types of cancer. However,
information about whether shared neoantigens can induce their specific cytotoxic T cells
is still very limited. One of the first reports of shared neoantigens is that T cells reactive
to KRAS G12D-derived peptide presented on human leukocyte antigen (HLA)-C*08:02
were identified in TILs from a pancreatic cancer patient [10]. They observed objective
regression of lung metastases after the infusion of TILs composed of T cell clones that
specifically targeted KRAS G12D [12] or TCR-engineered T cells targeting KRAS G12D on
HLA-C*08:02 [13]. However, targetable patients by this KRAS G12D shard neoantigen were
limited due to the low frequency of the HLA-C*08:02 allele. Shared neoantigens derived
from TP53 hotspot mutations have also been identified, including R175H (presented on
HLA-A*02:01), Y202C (HLA-A*02:01), and R248W (HLA-A*68:01) in TILs from patients
with epithelial cancers [14,15]. Although HLA-A*02:01 is the most common HLA allele
in Caucasians, the total frequency of these three TP53 mutations is less than 5% in the
pan-cancer population. Thus, more extensive screenings and identification of targetable
shared neoantigens are required to apply this concept to a clinical setting.
In the present study, we attempted to comprehensively screen shared neoantigens
derived from recurrent somatic mutations observed in 10,182 exome sequencing data in
the Cancer Genome Atlas (TCGA) and identified a peptide derived from FGFR3 Y373C,
which is frequent in bladder cancer, as a candidate of shared neoantigens. Here, we report
the establishment of genetically engineered FGFR3Y373C -specific TCR-T cells and their
cytotoxic functions.
2. Materials and Methods
2.1. Cell Lines and Antibodies
We purchased C1R (B lymphoblasts lacking endogenous human leukocyte antigen
(HLA)-A and HLA-B expression), Jiyoye, and EB-3 cells from the American Type Culture
Collection (Rockville, MD, USA) and cultured them in RPMI1640 supplemented with
10% FBS. We developed C1R cells stably expressing HLA-A*02:01 or HLA-A*24:02 (C1RA0201 or C1R-A2402, respectively) in our previous study [4]. We generated C1R-A0206,
C1R-A1101, C1R-A3101, and C1R-A3303 by the nucleofection of pCAGGS vectors encoding
HLA-A*02:06, HLA-A*11:01, HLA-A*31:01, and HLA-A*33:03 cDNAs, respectively. ...

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