Recurrent Neoantigens in Colorectal Cancer as Potential Immunotherapy Targets

Chen, Chao; Liu, Songming; Qu, Ruokai; Li, Bo

doi:10.1155/2020/2861240

Cited by 16 publications

(16 citation statements)

References 41 publications

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“…Thus, the patients' cytotoxic properties seemed consistent with the mutational and clinical course of the neoplastic progeny. The mutated KRAS G12D and G12V have been reported as recurrent neoantigens in CRC, and this supports the hypothesis about the role of immune-mediated clonal selection in the above patients (20), which deserves further studies to be definitely addressed.…”

Section: Discussionsupporting

confidence: 78%

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Ottaiano

d’Aragona²,

Trotta³

et al. 2022

Front. Immunol.

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BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan–Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02–0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies.

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Section: Discussionsupporting

confidence: 78%

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Ottaiano

d’Aragona²,

Trotta³

et al. 2022

Front. Immunol.

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“…found that indel-related neoantigens covered a large proportion of MSI-H CRC patients. 35 About 10 to 20 neoantigen peptides are usually synthesized simultaneously to prepare vaccines or other immunotherapy products. 10 Jitske et al .…”

Section: Discussionmentioning

confidence: 99%

Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer

Zhang

et al. 2021

Human Vaccines & Immunotherapeutics

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Neoantigens play a crucial role in cancer immunotherapy. However, the effectiveness and safety of neoantigen-based immunotherapies in patients with colorectal cancer (CRC), particularly in the Chinese population, have not been well studied. This study explored the feasibility and effectiveness of neoantigens in the treatment of CRC. Whole-exome sequencing (WES) and transcriptome sequencing were used to identify somatic mutations, RNA expression, and human leukocyte antigen (HLA) alleles. Neoantigen candidates were predicted, and immunogenicity was assessed. The neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D from Patient 4 (PW4); TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I, and NAV2-D1973N from Patient 10 (PW10); and HAVCR2-F39V, SEC11A-R11L, SMPDL3B-T452M, LRFN3-R118Q, and ULK1-S248L from Patient 11 (HLA-A0201 + PW11) induced a heightened neoantigen-reactive T cell (NRT) response as compared with the controls in peripheral blood lymphocytes (PBLs) isolated from patients with CRC. In addition, we identified neoantigen-containing peptides SEC11A-R11L and ULK1-S248L from HLA-A0201 + PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201 + PW11 as well as in HLA-A2.1/K b transgenic mice. Importantly, adoptive transfer of NRTs induced by vaccination with two mutant peptides could effectively inhibit tumor growth in tumor-bearing mouse models. These data indicate that neoantigen-containing peptides with high immunogenicity represent promising candidates for peptide-mediated personalized therapy. Abbreviations: CRC: colorectal cancer; DCs: dendritic cells; ELISPOT: enzyme-linked immunosorbent spot; E:T: effector:target; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mut: mutant type; NGS: next-generation sequencing; NRTs: neoantigen-reactive T cells; PBMCs: peripheral blood mononuclear cells; STR: short tandem repeat; PBLs: peripheral blood lymphocytes; PBS: phosphate-buffered saline; PD-1: programmed cell death protein 1; TILs: tumor-infiltrating lymphocytes; RNA-seq: RNA sequencing; Tg: transgenic; TMGs: tandem minigenes; WES: whole-exome sequencing; WT: wild-type.

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“…Recently, it has been reported that single-nucleotide variants (SNVs) in genes, such as KRAS, PIK3CA, PCBP1, and CHEK2, are associated with the production of the 10 most frequent neoantigens. An analysis of the published CRC WES data has enabled a more complete map of CRC mutations to be produced, which indicated that high-frequency mutations such as KRAS G12D, KRAS G12V, PIK3CA E545K, PIK3CA H1047R, and BMPR2 N583Tfs ∗ 44 can combine with HLA and be presented [ 68 ]. However, recent findings indicate that this selection of mutated driver genes may have weak binding affinity with MHC molecules during the development of tumors.…”

Section: Neoantigens and Immune Response In Colorectal Cancermentioning

confidence: 99%

Neoantigen: A Promising Target for the Immunotherapy of Colorectal Cancer

Zheng

Wang

et al. 2022

Disease Markers

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At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such “cold tumors” with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC.

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Recurrent Neoantigens in Colorectal Cancer as Potential Immunotherapy Targets

Cited by 16 publications

References 41 publications

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer

Neoantigen: A Promising Target for the Immunotherapy of Colorectal Cancer

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