Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma

Oliveira, Giacomo; Stromhaug, Kari; Klaeger, Susan; Kula, Tomasz; Frederick, Dennie T.; Le, Phuong M.; Forman, Juliet; Huang, Teddy; Li, Shuqiang; Zhang, Wandi; Xu, Qikai; Cieri, Nicoletta; Clauser, Karl R.; Shukla, Sachet A.; Neuberg, Donna; Justesen, Sune; MacBeath, Gavin; Carr, Steven A.; Fritsch, Edward F.; Hacohen, Nir; Sade-Feldman, Moshe; Livak, Kenneth J.; Boland, Genevieve M.; Ott, Patrick A.; Keskin, Derin B.; Wu, Catherine J.

doi:10.1038/s41586-021-03704-y

Cited by 273 publications

(325 citation statements)

References 37 publications

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“…CD8 + T cell clones linked to exhaustion are enriched within the tumor parenchyma, where the local cytokine and chemokine milieu varies dramatically from the surrounding stroma where less exhausted CD8 + T cell clones are found. Based on these findings, our data support a model in which CD8 + T cells infiltrate the TME of brain metastases in an antigen-independent manner 38 . Once CD8 + T cells are retained in the tumor, antigen signaling, or lack thereof, drives recruitment of CD8 + T cells to spatial niches within the TME.…”

Section: Discussionsupporting

confidence: 86%

“…Tumor-specific exhausted progenitor TCF-1 + CD8 + T cells have been found in human papillomavirus positive (HPV+) head and neck squamous cell carcinoma 35 , which grows in oropharyngeal lymphoid tissues. 36 Similar progenitor cells were also recently identified in melanoma and non-small cell lung cancers, where a majority of tumor-specific CD8 + T were in a terminally differentiated state 37,38 . In murine models, antigen-specific exhausted progenitor CD8 + T cells are enriched in tumor-draining lymph nodes and are found exclusively in secondary lymphoid organs during chronic infection 39–41 .…”

Section: Introductionsupporting

confidence: 56%

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The CD8⁺ T cell landscape of human brain metastases

Sudmeier

Hoang

Nduom

et al. 2021

Preprint

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Despite improved outcomes with checkpoint blockade immunotherapy, patients with brain metastases have the worst prognosis among patients with metastatic cancer. Immune checkpoint blockade agents target inhibitory receptors, such as PD-1, on exhausted CD8+ T cells to restore their anti-cancer function. Many patients, however, either do not respond or progress after an initial response to immune checkpoint blockade, and distant intracranial failure is common despite excellent options for local treatment of brain metastasis. To develop more effective therapeutic strategies for the treatment of brain metastases, an understanding of the phenotype of brain metastasis-infiltrating CD8+ T cells is essential. Here we performed a detailed characterization of the CD8+ T cells contained in brain metastases. Brain metastases were densely infiltrated by CD8+ T cells; blood contamination of tumor samples was rare. Compared to patient-matched circulating cells, brain metastasis-infiltrating CD8+ T cells had a distinct phenotype characterized by more frequent expression of PD-1, with subpopulations defined by expression of additional co-inhibitory molecules and the residence marker CD69. Single cell RNA-sequencing identified four phenotypic subpopulations within brain metastasis-infiltrating PD-1+ CD8+ T cells. Two of these populations — a terminally-differentiated and a dividing population — were characterized by high expression of co-inhibitory molecules and lacked expression of progenitor markers such as TCF-1. There was significant T cell receptor (TCR) overlap between the terminally-differentiated and dividing populations, suggesting that the dividing cells give rise to the terminally-differentiated cells. There was minimal TCR overlap between these two populations and other brain metastasis-infiltrating PD-1+ CD8+ T cells. T cell clones from brain metastasis-infiltrating CD8+ T cells were rare in circulation, particularly clones from the terminally-differentiated and dividing populations. We systematically identified bystander CD8+ T cells specific for microbial antigens; these cells infiltrated brain metastases and expressed genes shared with exhausted progenitor CD8+ T cells, such as TCF7 and IL7R. We performed spatial transcriptomics on brain metastases and used a novel method to obtain TCR sequences from spatial transcriptomics data. These data revealed distinct niches within the TME defined by their gene expression patterns and cytokine profiles. Terminally-differentiated CD8+ T cells preferentially occupied niches within the tumor parenchyma. Together, our results show that antigen-specificity restricts the spatial localization, phenotypic states, and differentiation pathways available to CD8+ T cells within the brain metastasis TME.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionsupporting

confidence: 56%

The CD8⁺ T cell landscape of human brain metastases

Sudmeier

Hoang

Nduom

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Many T CD8 TILs in melanoma are bystander cytotoxic lymphocytes with a TCR specificity for viral antigens (V-spe), while only a minority represent true tumor-antigen-specific (T-spe) lymphocytes [55]. Among such CD8 TILs, the V-spe clonotypes prominently display functional Tcm and Tem differentiation stages whereas the majority of T-spe clonotypes are dysfunctional Tex cells [56]. In parallel, we found that HPV-positive HNSCC and EBV-positive HL patients have γδ TILs that are more prone to recirculate from the tumor and avoid exhaustion.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease

Cerapio

Perrier

Pont

et al. 2021

Viruses

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The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein–Barr virus-positive Hodgkin’s lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.

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“…High-throughput approaches for screening hundreds of sequenced TCRs for tumor antigen recognition have now been developed, which will facilitate truly personalized TCR-T cell therapies. The antigen specificity of various cloned TCRs extracted from TIL and/or PBMC can be assessed by co-culturing them with Epstein-Barr virus-immortalized lymphoblastoid cell lines pulsed with hundreds of peptides corresponding to personalized neoantigens (NeoAgs), various TAAs, or common viral antigens such as HLA-I immunopeptidomes [71]. In a more unbiased approach, NeoAgs can also be expressed as mini-genes in autologous antigen-presenting cells to assess panels of TCRs for antigen reactivity [63,72].…”

Section: Tcr Cloning and Validation Approachesmentioning

confidence: 99%

Evolution of CD8+ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

Sun

Sonnemann

et al. 2021

Cells

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Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis antigens. With recent technological developments, it has become feasible to target neoantigens derived from tumor somatic mutations, which represents a highly personalized therapy, since most neoantigens are patient-specific and are rarely shared between patients. TCR-T therapies have been tested for clinical efficacy in treating solid tumors in many preclinical studies and clinical trials all over the world. However, the efficacy of TCR-T therapy for the treatment of solid tumors has been limited by a number of factors, including low TCR avidity, off-target toxicities, and target antigen loss leading to tumor escape. In this review, we discuss the process of deriving tumor antigen-specific TCRs, including the identification of appropriate tumor antigen targets, expansion of antigen-specific T cells, and TCR cloning and validation, including techniques and tools for TCR-T cell vector construction and expression. We highlight the achievements of recent clinical trials of engineered TCR-T cell therapies and discuss the current challenges and potential solutions for improving their safety and efficacy, insights that may help guide future TCR-T studies in cancer.

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Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma

Cited by 273 publications

References 37 publications

The CD8⁺ T cell landscape of human brain metastases

The CD8⁺ T cell landscape of human brain metastases

Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease

Evolution of CD8+ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

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Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma

Cited by 273 publications

References 37 publications

The CD8+ T cell landscape of human brain metastases

The CD8+ T cell landscape of human brain metastases

Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease

Evolution of CD8+ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

Contact Info

Product

Resources

About

The CD8⁺ T cell landscape of human brain metastases

The CD8⁺ T cell landscape of human brain metastases