Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes

Gros, Alena; Tran, Eric; Parkhurst, Maria R.; Ilyas, Sadia; Pasetto, Anna; Groh, Eric; Robbins, Paul F.; Yossef, Rami; Garcia-Garijo, Andrea; Fajardo, Carlos Alberto; Prickett, Todd D.; Li, Jia; Gartner, Jared J.; Ray, Satyajit; Ngo, Lien T.; Wunderllich, John R.; Yang, James Chih‐Hsin; Rosenberg, Steven A.

doi:10.1172/jci127967

Cited by 124 publications

(93 citation statements)

References 46 publications

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“…These findings provide a method to pre-select ovarian tumor-specific T cells directly from tumor infiltrates, without the need for complex immunological screening technologies that require antigen prediction/identification to evaluate T cells. Recently, it has been shown that PD-1 also allows the identification of tumor-specific T cells in MMR-proficient gastrointestinal cancer patients [23]. This finding together with our results indicate that the utility of PD-1 to select for tumor-specific T cells is not restricted to highly immune-reactive tumors [11,13,14,24].…”

Section: Discussionsupporting

confidence: 79%

The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

Salas‐Benito

Conde²,

Tamayo-Uria³

et al. 2020

Preprint

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Background: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as programmed cell death protein 1 (PD-1), for tumor-specific T-cell enrichment, as well as predictive biomarkers that help identify those patients capable of rendering tumor-reactive TIL products. We have investigated this in ovarian cancer (OC) patients as candidate for TIL therapy implementation. Methods: PD-1- and PD-1+ CD8 TILs were isolated from resected ovarian tumors and, after polyclonal expansion, TIL products were tested against autologous tumor cells. Reactivity was assessed by IFNg production (ELISPOT) and upregulation of CD137. Baseline tumor samples were examined using flow cytometry, multiplexed quantitative immunofluorescence, Nanostring technology, for gene expression profile (GEP) analyses, as well as a next generation sequencing gene panel, for tumor mutational burden (TMB) calculation, to identify those features that distinguished patients with tumor-reactive and non-tumor-reactive TIL products.Results: Tumor-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Flow-cytometric studies revealed that fresh tumors from patients rendering tumor-reactive TILs presented a significantly higher frequency of CD137+ cells within the PD1+CD8+ subset. Multiplexed immunofluorescence supported this finding, which was particularly striking in intraepithelial CD8 TILs. Baseline GEP analysis showed that patients rendering tumor-reactive TILs exhibited a significantly higher T-cell inflamed signature. Despite no correlation between TMB and GEP, both parameters stratified tumors, with patients with higher TMB and/or T-cell inflamed signature score rendering tumor-reactive TILs. Conclusion: We have demonstrated that PD-1 identifies autologous-tumor specific CD8 T cells infiltrating ovarian tumors and have uncovered predictive factors that identify OC patients who are likely to render tumor-reactive cells from PD-1+ TILs. These findings have important implications for improving the efficacy of TIL therapy in OC.

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Section: Discussionsupporting

confidence: 79%

The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

Salas‐Benito

Conde²,

Tamayo-Uria³

et al. 2020

Preprint

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“…For example, CD8 T cells targeting mutant KRAS [115] or TP53 "Hotspot" Mutations [116] have been identified. Moreover, circulating PD-1 + lymphocytes have recently been shown to recognize human gastrointestinal cancer neoantigens [117].…”

Section: Why Immunotherapy?mentioning

confidence: 99%

Immunotherapy, Inflammation and Colorectal Cancer

Lichtenstern

Ngu

Shalapour

et al. 2020

Cells

213

154

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Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR–MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR–MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

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“…They used high-sensitivity MS to analyze exome statistics, and through this method, they discovered tumor-specific neoantigens in selected patients that were validated by the evidence of potent patientderived neoantigen-specific antitumor immune responses (36). Gros et al used WES to find non-synonymous mutations in metastatic gastrointestinal cancer with low mutational burden, and further synthesized these mutated peptides or tandem minigenes to pulse into Antigen Presenting Cells (APC), which could enrich the circulating CD8 + /PD-1 +/hi and CD4 + PD-1 +/hi T cells harboring neoantigen reactive TCR from cancer patients (37).…”

Section: The Applications Of Wes/msmentioning

confidence: 99%

Adoptive Cell Therapy Targeting Neoantigens: A Frontier for Cancer Research

2020

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Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR), and ACT has made a great difference in treating multiple types of tumors. ACT is not perfect, and it can be followed by severe side effects, which hampers the application of ACT in clinical trials. One of the most promising methods to minimize side effects is to endow adoptive T cells with the ability to target neoantigens, which are specific to tumor cells. With the development of antigen screening technologies, more methods can be applied to discover neoantigens in cancer cells, such as whole-exome sequencing combined with mass spectrometry, neoantigen screening through an inventory-shared neoantigen peptide library, and neoantigen discovery via trogocytosis. In this review, we focus on the side effects of existing antigens and their solutions, illustrate the strategies of finding neoantigens in CART and TCR-T therapies through methods reported by other researchers, and summarize the clinical behavior of these neoantigens.

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Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes

Cited by 124 publications

References 46 publications

The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

Immunotherapy, Inflammation and Colorectal Cancer

Adoptive Cell Therapy Targeting Neoantigens: A Frontier for Cancer Research

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