Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers

Yossef, Rami; Krishna, Sri; Sindiri, Sivasish; Lowery, Frank J.; Copeland, Amy R.; Gartner, Jared J.; Parkhurst, Maria R.; Parikh, Neilesh B.; Hitscherich, Kyle J.; Levi, Shoshana T.; Chatani, Praveen D.; Zacharakis, Nikolaos; Levin, Noam; Vale, Nolan R.; Nah, Shirley K.; Dinerman, Aaron; Hill, Victoria K.; Ray, Satyajit; Bera, Alakesh; Levy, Lior; Jia, Li; Kelly, Michael C.; Goff, Stephanie L.; Robbins, Paul F.; Rosenberg, Steven A.

doi:10.1016/j.ccell.2023.11.005

Cited by 15 publications

(20 citation statements)

References 54 publications

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“…These cells can be identified and isolated from blood for further characterization using in vitro assays to develop new therapies. Our study is in line with the recent publication by Yossef et al, who report that the signature of tumor-specific CD8 T cells in blood shares similarities with their counterparts in tissues and could therefore be an alternative source for identifying antitumor T cell reactivity 41 .…”

Section: Discussionsupporting

confidence: 92%

The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases

Cardon,

Guinebretière,

Dong

et al. 2024

Preprint

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Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells may play a central role. However, self-antigen-specific CD4 T cells are mainly characterized in the bloodstream, and the link with the immune response in the targeted tissue is a difficult and under-studied task in AILD. We hypothesize that circulating self-antigen-specific CD4 T cells contain dominant hepatic CD4 T cell clonotypes and represent liver-derived autoreactive CD4 T cells. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells reveal a specific B-helper and immuno-exhausted transcriptional profile, which is conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. The dominant hepatic CD4 T cell clones shared a similar transcriptomic signature and were enriched in the circulating PD1+ TIGIT+ HLA-DR+ CD4 T cell subset. In liver biopsy, PD1+ CD4 T cells were present in tertiary lymphoid structure, reinforcing the hypothesis of a pathogenic role of these cells. Using a mouse model, we demonstrated antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Inhibition of immune checkpoint molecules contributed to increased hepatic damages in a CD4 T cell dependent manner. This study reveals the origin of liver-autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment and recirculate from the damaged tissue during the active phase of the disease. In addition, this study also shows how immune checkpoint molecules contribute to local antigen-specific tolerance in the liver, which may be dysregulated in AILD and immunotherapy-induced acute hepatitis. Finally, our study enables tracking and isolating liver autoreactive CD4 T cells in future diagnostic and therapeutic purposes.

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Section: Discussionsupporting

confidence: 92%

The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases

Cardon,

Guinebretière,

Dong

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…1H). Our ndings are thereby consistent with prior work showing that tumor antigen-speci c T cells in the blood are predominantly a clonally expanded, cytotoxic CD8 + T cell population 7,[10][11][12]14 .…”

Section: Circulating Tumor Antigen Reactive T Cells Are Predominantly...supporting

confidence: 92%

“…4E). While the demonstrated reactivity was limited to a minority of clonotypes, which is in line with work by others 5,6,10,29,30,[33][34][35] , these data suggest that at least a subpopulation of KIR + CD8 + T cells are tumor antigen-speci c.…”

Section: Functional Con Rmation Of Tumor Antigen Reactivity In Kir + ...supporting

confidence: 90%

“…Consistent with prior work, circulating predicted-reactive CD8 + T cells were concentrated in clusters with high cytotoxicity (CD8.1, CD8.2, CD8.4), high NK-associated markers (CD8.6), and which largely resembled terminally differentiated effector CD8 + T cells based on reference mapping ( g. S3), although they could be detected across nearly all transcriptional CD8 + clusters (Fig. 1C) 7,8,10,12 . In contrast, circulating CD4 + T cells were largely concentrated in clusters highly expressing PASK, IL7R, and SELL (CD4.3, CD4/CD8.1), consistent with central/effector memory-like phenotypes.…”

Section: Circulating Tumor Antigen Reactive T Cells Are Predominantly...supporting

confidence: 89%

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Circulating Tumor Reactive KIR+CD8+ T cells Suppress Anti-Tumor Immunity in Patients with Melanoma

Hafler,

Lu,

Lucca

et al. 2024

Preprint

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Effective anti-tumor immunity is largely driven by cytotoxic CD8+ T cells that can specifically recognize tumor antigens. However, the factors which ultimately dictate successful tumor rejection remain poorly understood. Here we identify a subpopulation of CD8+ T cells which are tumor antigen-specific in patients with melanoma but resemble KIR+CD8+ T cells with a regulatory function (Tregs). These tumor antigen-specific KIR+CD8+ T cells are detectable in both the tumor and the blood, and higher levels of this population are associated with worse overall survival. Our findings therefore suggest that KIR+CD8+ Tregs are tumor antigen-specific but uniquely suppress anti-tumor immunity in patients with melanoma.

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“…Previous studies have demonstrated that functional recognition of tumor-specific antigens by surface TCRs can be assessed in vitro cultured TILs. However, the non-specific expression on paracrine TILs may impact the accuracy of antitumor TIL recognition ( 137 ). The utilization of innovative peptides loaded with human leukocyte antigen (HLA) protein multimers to identify neoantigen-reactive T cells necessitates patient-specific investigations and is subject to certain limitations ( 137 ).…”

Section: Targeting Tumor Specific Neoantigensmentioning

confidence: 99%

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances

Wang,

Yuan,

et al. 2024

Front. Immunol.

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The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.

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Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers

Cited by 15 publications

References 54 publications

The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases

The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases

Circulating Tumor Reactive KIR+CD8+ T cells Suppress Anti-Tumor Immunity in Patients with Melanoma

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances

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