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Cancer neoantigens produced by tumor mutations can trigger tumor-specific T cell responses, which greatly enhance the benefits of cancer immunotherapy patients [1], so increasing the number of neoantigen response T cells or improving their activity has become a hot issue
of concern.
Due to the patient-specific nature of neoantigens [2], the identification of neoantigens recognized by T cells in individual patients has long been a challenge
.
Previous methods have limited antigen identification to specific HLA genotypes [3-6], ignoring the breadth of
neoantigen profiles.
CD4+ T cells, which are also important in immunotherapy, have been studied very little compared to CD8+ T cells, so it is important
to develop an HLA unbiased tool for identifying T cells recognizing neoantigens in individual patients.
On January 2, 2023, Emile E.
Voest, Ton N.
Schumacher and Wouter Scheper from the Department of Molecular Oncology and Immunology at the Netherlands Cancer Institute collaborated to present a report entitled Identification of patient-specific in Nature Biotechnology CD4+and CD8+T cell neoantigens through HLA-unbiased genetic screens, they established a genetic neoantigen screening system HANSolo (HLA-Agnostic Neoantigen Screening), which enables sensitive identification of neoantigens
recognized by CD4+ and CD8+ T cells in a patient's intact HLA genotype.
The authors first verified the feasibility and sensitivity of the method in known TCR-specific neonatal antigens (TCR #53, TCRs DMF4 & DMF5).
。 The designed model antigen library containing 4,764 microgenes was optimized to enable the screening of complete mutation profiles of all human highly mutagenic burden tumors
.
The authors mixed different T cells expressing DMF4, DMF5, or 1D3 TCR and analyzed them and found that specific epitopes could be reliably identified
.
So far, the effectiveness of the genetic screening method proposed in this paper in the discovery of MHC type I neoantigen has been demonstrated, and this technique can be used to distinguish the activity of TCR-pMHC interaction, and is also suitable for different cloned T cell populations
.
Similarly, the authors measured the suitability
of HANSolo in the discovery of MHC type II neoantigens recognized by CD4+ T cells.
Compared with the existing genetic screening technology, HANSolo can identify any type of allele-defined T cell epitope in the individual, and its practicality has been verified in the corresponding experiments, and through the analysis of the reactivity of tumor-infiltrating lymphocyte neoantigen in the same patient, the authors found that HANSolo has advantages
in mining neoantigens.
Figure 1 Method Overview
Next, the authors evaluated the value of the system applied to neoantigen discovery in cancer patients, identifying tumor mutations in melanoma and constructing a patient mutant panel library containing 2,562 microgenes, for CD4+ and CD8+ Tumor-infiltrating T cells were screened, and 6 potential CD8+ T cell recognized neoantigens and 1 CD4+ T cell recognized neoantigen were found, respectively, and the recognition of 5 epitopes was verified
.
Consistent with what was observed in previous model antigen screening, the level of epitope deletion correlates with
the ability of patient T cells to produce interferon γ.
In non-small cell lung cancer, the authors also detected CD8+ T cells
that respond to neoantigens.
Recent studies have shown that the culture of patient tumor organoids or antigen-presenting cells expressing antigens can enrich tumor-specific T cell populations, so can this strategy be used for the newly proposed method? The authors made corresponding explorations in microsatellite unstable colorectal cancer, and used CD8+ T cell products generated from in vitro cultures of peripheral blood mononuclear cells of tumor organoids to screen the patient's mutant group, and identified two neoantigens
recognized by T cells.
So far, the effectiveness of the screening method has been verified
in all tested patients.
In summary, this paper presents a high-throughput genetic system for the identification of neoantigens recognized by T cells in individuals, realizes unbiased screening specific for T cells of all MHC genotypes, is feasible in large genetic libraries, and exhibits sensitivity and throughput superior to existing methods, especially for neoantigens recognized by CD4+ T cells
。
Original link:
https://doi.
org/10.
1038/s41587-022-01547-0
Platemaker: Eleven
References
1.
Schumacher, T.
N.
, Scheper, W.
& Kvistborg, P.
Cancer neoantigens.
Annu.
Rev.
Immunol.
37, 173–200 (2018).
2.
Schumacher, T.
N.
& Schreiber, R.
D.
Neoantigens in cancer immunotherapy.
Science 348, 69–74 (2015).
3.
Bentzen, A.
K.
et al.
Large-scale detection of antigen-specificT cells using peptide-MHC-I multimers labeled with DNAbarcodes.
Nat.
Biotechnol.
34, 1037–1045 (2016).
4.
Kula, T.
et al.
T-Scan: a genome-wide method for the systematicdiscovery of T cell epitopes.
Cell 178, 1016–1028.
e13 (2019).
5.
Joglekar, A.
V.
et al.
T cell antigen discovery via signaling andantigen-presenting bifunctional receptors.
Nat.
Methods 16,191–198 (2019).
6.
Li, G.
et al.
T cell antigen discovery via trogocytosis.
Nat.
Methods16, 183–190 (2019).
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