Induction of neoantigen-reactive T cells from healthy donors

Ali, Muhammad; Foldvari, Zsofia; Giannakopoulou, Eirini; Böschen, Maxi Lu; Strønen, Erlend; Yang, Weiwen; Toebes, Mireille; Schubert, Benjamin; Kohlbacher, Oliver; Schumacher, Ton N.; Olweus, Johanna

doi:10.1038/s41596-019-0170-6

Cited by 81 publications

(89 citation statements)

References 217 publications

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“…T cells targeting mutations can be detected from tumor infiltrating lymphocytes (TILs), peripheral memory lymphocytes of cancer patients and peripheral naïve lymphocytes of healthy donors [12, 26]. However, except mouse model, PBMCs from healthy donors were easier obtained to determine the immunogenicity of the predicted neoantigens, comparing to that from patients.…”

Section: Resultsmentioning

confidence: 99%

“…However, the remaining neo-peptides were not detected in our system. Recently, Muhammad Ali et al proved that minimizing the formation of irrelevant immunogenic peptides could increase the targeted epitopes to bind HLA, and the order of arranged epitopes in the tandem minigene were involved in the efficiency of antigen presentation [26]. In our present study, the predicted neoantigens in the tandem minigene each had 27 amino acids with the mutation at position 14 (Table 2), which may result in the formation of other high-affinity irrelevant and competitive presented peptides, and were randomly combined in the tandem minigene.…”

Section: Discussionmentioning

confidence: 99%

“…The immunogenicity of predicted neoantigens is usually detected through the response of TIL [11, 12]. Moreover, although the frequency of the neoantigen-reactive T cells in the peripheral blood is quiet low compared with that in the tumor sample, neoantigen-specific T cells, which derive from circulating CD8 + memory T cells of cancer patients or circulating CD8 + naïve T cells of healthy donors, can be enriched after being in vitro co-cultured with the cognate DCs pre-loaded neoantigens, and their response to recognize the corresponding neoantigens can be detected by conventional experimental methods [12, 26, 41]. Therefore, we generally adopted one of the proven methods to detect the immunogenicity of our predicted neoantigens, in which the circulating bulk CD8 + T cells from one healthy donor were stimulated for two rounds by cognate DCs pre-loaded neoantigens.…”

Section: Discussionmentioning

confidence: 99%

“…As approximately only one in 10 5 -10 6 T cells is specific for a given antigen in the lymph node, and circulating CD8 + memory T cells from healthy donors do not contribute to the production of neoantigen-responsive T cells, to enrich circulating CD8 + naïve T cells from healthy donors before priming can enhance the probability of specific T cells encountering DCs presenting the cognate neoantigen [26, 42]. Based on the donor-dependent variability and sufficient diversity of the human TCR repertoire, several donors need to be screened for identifying the immunogenicity of a novel candidate neoantigen [26]. Therefore, we considered that CTL, which were expanded from CD8 + naïve T cells of other healthy donors, may respond to the remaining immunogenic negative neo-peptides.…”

Section: Discussionmentioning

confidence: 99%

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The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

Liang

Qin

et al. 2019

Preprint

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23Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the 24 world, as the result of the traditional treatments. Immunotherapy targeting neoantigens 25 can induce durable tumor regression in cancer patients, but is almost limited to 26 individual treatment, resulting from the unique neoantigens. Many shared oncogenic 27 mutations are detected, but whether the common neoantigens can be identified in CRC 28 is unknown. Using the somatic mutations data from 321 CRC patients combined with 29 a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-30 A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and 31 presentation score (EPIC>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 32 25 common neoantigens were proved to be naturally processed and presented on 33 constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common 34 neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) 35 to secrete IFN-. However, only 2 out of 25 common neoantigens were simultaneously 36 presented and immunogenic. Moreover, using cell-sorting technology combined with 37 single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 38 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens 39 with presentation and immunogenicity could be found in CRC, which would be 40 developed as the universal targets for CRC immunotherapy. 41 42 43 44 45 46 Colorectal cancer (CRC) is the third commonest diagnosed malignant cancer and 47 the second leading cause of cancer death in the world [1]. In 2018, more than 1.8 48 million new cases of CRC and almost 881 thousand cases of CRC-interrelated death 49 occurred in the world [1], and the global burden of CRC is estimated to reach over 2.2 50 million new cases and 1.1 million cancer deaths by 2030 [2]. Traditionally surgical 51 resection can cure the early stage of CRC, but about 50% of patients ultimately die of 52 distant metastases. While chemotherapy, radiation therapy and targeted therapy can 53 extend overall survival, less than 15% of patients with metastatic CRC survive 54 beyond 5 years [3]. Therefore, the novel and more effective therapeutic approaches 55 for CRC are necessary to develop. 56 In the recent years, based on a better knowledge of the complex interactions 57 between the immune system and the tumor microenvironment, immunotherapy has 58 become a novel effective and promising therapeutic strategy for cancer, and its 59 efficacy was widely tested by CRC model. The vast majority of CRC patients with 60 deficient mismatch repair (dMMR) or highly microsatellite instable (MSI-H) benefit 61 from immune checkpoint inhibitors, which is not effective in other CRC patients with 62 proficient MMR (pMMR) or microsatellite stable (MSS) [4]. Patients with CRC do 63 not respond to autologous tumour lysate DC (ADC) and peptide vaccines [4]. T cells, 64 which are engineered to express an affinity-enhanced T-cell rece...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

Liang

Qin

et al. 2019

Preprint

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show abstract

“…At the same time, the combination of tumor vaccines with other traditional therapies, such as chemoradiotherapy and targeted therapy, show immense potential for development. In addition, Muhammad et al [162] adopted a different strategy for this problem recently. They transfected monocyte derived DC with neoantigen encoding mRNA to prime autologous naive CD8+ T cells in healthy donors.…”

Section: Disadvantages and Future Directionsmentioning

confidence: 99%

Neoantigen vaccine: an emerging tumor immunotherapy

et al. 2019

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Genetic instability of tumor cells often leads to the occurrence of a large number of mutations, and expression of non-synonymous mutations can produce tumor-specific antigens called neoantigens. Neoantigens are highly immunogenic as they are not expressed in normal tissues. They can activate CD4+ and CD8+ T cells to generate immune response and have the potential to become new targets of tumor immunotherapy. The development of bioinformatics technology has accelerated the identification of neoantigens. The combination of different algorithms to identify and predict the affinity of neoantigens to major histocompatibility complexes (MHCs) or the immunogenicity of neoantigens is mainly based on the whole-exome sequencing technology. Tumor vaccines targeting neoantigens mainly include nucleic acid, dendritic cell (DC)-based, tumor cell, and synthetic long peptide (SLP) vaccines. The combination with immune checkpoint inhibition therapy or radiotherapy and chemotherapy might achieve better therapeutic effects. Currently, several clinical trials have demonstrated the safety and efficacy of these vaccines. Further development of sequencing technologies and bioinformatics algorithms, as well as an improvement in our understanding of the mechanisms underlying tumor development, will expand the application of neoantigen vaccines in the future.

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Neo‐Antigen‐Reactive T Cells Immunotherapy for Colorectal Cancer: A More Personalized Cancer Therapy Approach

Chen,

Kong,

Lin

2023

Global Challenges

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Colorectal cancer (CRC) is the second most common malignancy in women and the third most frequent cancer in men. Evidence has revealed that the survival of patients with metastatic CRC is very low, between one and three years. Neoantigens are known proteins encoded by mutations in tumor cells. It is theorized that recognizing neoantigens by T cells leads to T cell activation and further antitumor responses. Neoantigen‐reactive T cells (NRTs) are designed against the mentioned neoantigens expressed by tumor cells. NRTs selectively kill tumor cells without damage to non‐cancerous cells. Identifying patient‐specific and high immunogen neoantigens is important in NRT immunotherapy of patients with CRC. However, the main challenges are the side effects and preparation of NRTs, as well as the effectiveness of these cells in vivo. This review summarized the properties of neoantigens as well as the preparation and therapeutic outcomes of NRTs for the treatment of CRC.

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Induction of neoantigen-reactive T cells from healthy donors

Cited by 81 publications

References 217 publications

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

Neoantigen vaccine: an emerging tumor immunotherapy

Neo‐Antigen‐Reactive T Cells Immunotherapy for Colorectal Cancer: A More Personalized Cancer Therapy Approach

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