γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors

Harmon, Cathal; Zaborowski, Alexandra; Moore, Heather; Louis, Pamela St.; Slattery, Karen; Duquette, Danielle; Scanlan, James M.; Kane, Harry; Kunkemoeller, Britta; McIntyre, Claire; Scannail, Aine Ni; Moran, Bruce; Anderson, Ana C.; Winter, D. C.; Brennan, Donal J.; Brehm, Michael A.; Lynch, Lydia

doi:10.1038/s43018-023-00589-w

Cited by 20 publications

(26 citation statements)

References 66 publications

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“…4b ). Additionally, we found no evidence of IL17A expression, which is consistent with multiple studies demonstrating that human Vδ1 + cells producing IL-17 are rare 10 , 11 , 23 , 36 , 60 , 61 . Thus, the expression of PD-1 by tissue-associated Vδ1 + cells occurred against a background of the cells’ strong and selective functional potentials.…”

Section: Resultssupporting

confidence: 92%

“…We identified five studies with publicly accessible aligned RNA sequencing (RNA-seq) data and matched clinical response criteria 30 – 34 from a recent review 35 and meta-analysis of CPI transcriptomic datasets 34 yielding a total of 216 suitable cases ( Methods ). Next, we assessed tumors for their expression of the TRDV1 gene, which is a widely accepted robust surrogate for Vδ1 + cells 10 , 11 , 13 , 36 because it encodes the Vδ1 TCR subunit and is commonly deleted in αβ T cells 37 . Approximately 40% of tumors (89 of 216; Methods ) had no detectable TRDV1 expression and this was conspicuously associated with a deficit of detectable TCRα and TCRβ V genes ( TRAV and TRBV ; Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Akin to skin and melanomas, steady-state lung tissue and non-small-cell lung cancer (NSCLC) also harbor a population of tissue-resident PD-1 + Vδ1 + cells 23 . Likewise, the presence of Vδ1 + cells in NSCLC is also associated with favorable clinical outcomes 23 , 36 . Moreover, anti-PD-1 and anti-PD-L1 CPI therapies are also effective in the treatment of NSCLC 62 .…”

Section: Resultsmentioning

confidence: 99%

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PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Davies,

Kamdar,

Woolf

et al. 2024

Nat Cancer

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Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Davies,

Kamdar,

Woolf

et al. 2024

Nat Cancer

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“…In other gynecologic malignancies, γδ T cell infiltration also appears to play a protective role ( Table 1 ). Similar predictive values were independently associated between high TRDV1 (expressed by Vδ1 γδ T cells) levels and improved survival in endometrial cancer [ 53 ]. Furthermore, in a recent clinical trial, patients with endometrial carcinosarcoma who did not progress after treatment with cabozantinib in combination with PD-1 blockade showed significantly higher proportions of activated tissue-resident (CD103 + CD69 + ) ɣδ T cells than progressors [ 54 ].…”

Section: Introductionmentioning

confidence: 87%

“…Consistent with all these observations, most studies in other human cancers have also identified γδ T cell infiltration with superior outcomes [ 7 ]. This includes lung [ 4 , 5 ], breast [ 8 ], hepatocellular [ 56 ], renal [ 6 ], gastric [ 57 ], head and neck [ 58 ], and bladder [ 59 ] cancers, in addition to melanoma [ 60 ]; however, there have been some conflicting reports regarding the role of γδ T cells in tumors such as colorectal cancer, with studies supporting anti-tumor [ 61 ] vs. tumor-promoting activities [ 53 ] ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Harnessing γδ T Cells against Human Gynecologic Cancers

Conejo-Garcia,

Anadon,

Lopez-Bailon

et al. 2024

Life

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Immuno-oncology has traditionally focused on conventional MHC-restricted αβ T cells. Yet, unconventional γδ T cells, which kill tumor cells in an MHC-unrestricted manner, display characteristics of effector activity and stemness without exhaustion and are nearly universally observed in human gynecologic malignancies, correlating with improved outcomes. These cells do not have a clear counterpart in mice but are also found in the healthy female reproductive tract. Interventions that modulate their in vivo activity, or cellular therapies utilizing γδ T cells as an allogeneic, “off-the-shelf” platform (e.g., for chimeric antigen receptor expression) hold significant potential against challenging tumors like ovarian cancer, which has been stubbornly resistant to the immune checkpoint inhibitors that change the landscape of other human tumors. Here, we discuss recent discoveries on the specific populations of γδ T cells that infiltrate human gynecologic cancers, their anti-tumor activity, and the prospect of redirecting their effector function against tumor cells to develop a new generation of immunotherapies that extends beyond the traditional αβ T cell-centric view of the field.

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γδ T cells in human colon adenocarcinomas comprise mainly Vδ1, Vδ2, and Vδ3 cells with distinct phenotype and function

Rodin,

Szeponik,

Rangelova

et al. 2024

Cancer Immunol Immunother

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AbstractΓδ T cell infiltration into tumours usually correlates with improved patient outcome, but both tumour-promoting and tumoricidal effects of γδ T cells have been documented. Human γδ T cells can be divided into functionally distinct subsets based on T cell receptor (TCR) Vδ usage. Still, the contribution of these different subsets to tumour immunity remains elusive. Here, we provide a detailed γδ T cell profiling in colon tumours, using mass and flow cytometry, mRNA quantification, and TCR sequencing. δ chain usage in both the macroscopically unaffected colon mucosa and tumours varied considerably between patients, with substantial fractions of Vδ1, Vδ2, and non-Vδ1 Vδ2 cells. Sequencing of the Vδ complementarity-determining region 3 showed that almost all non-Vδ1 Vδ2 cells used Vδ3 and that tumour-infiltrating γδ clonotypes were unique for every patient. Non-Vδ1Vδ2 cells from colon tumours expressed several activation markers but few NK cell receptors and exhaustion markers. In addition, mRNA analyses showed that non-Vδ1 Vδ2 cells expressed several genes for proteins with tumour-promoting functions, such as neutrophil-recruiting chemokines, Galectin 3, and transforming growth factor-beta induced. In summary, our results show a large variation in γδ T cell subsets between individual tumours, and that Vδ3 cells make up a substantial proportion of γδ T cells in colon tumours. We suggest that individual γδ T cell composition in colon tumours may contribute to the balance between favourable and adverse immune responses, and thereby also patient outcome.

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γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors

Cited by 20 publications

References 66 publications

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Harnessing γδ T Cells against Human Gynecologic Cancers

γδ T cells in human colon adenocarcinomas comprise mainly Vδ1, Vδ2, and Vδ3 cells with distinct phenotype and function

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