Research Topic

Next Generation γδ T Cell-Based Tumor Immunotherapy

About this Research Topic

γδ T cells represent an important class of “unconventional” T lymphocytes that play key roles in tumor immunosurveillance. With the increasing recognition of these cells as a clinical correlate for improved disease prognosis, there has been vast interest to harness their unique properties for therapeutic purposes. Seminal studies of Vγ9Vδ2 T cell activation by microbial or endogenous tumor-derived phosphoantigens have set the stage for its applications in targeting tumor. Subsequent discovery of the involvement of butyrophilin/butyrophilin-like proteins in regulating this specific immune reactivity have further paved the way for development of γδ T cell-based therapeutics. Concurrently, advances in understanding the specialized functions of γδ T cell subsets resident in various tissues have provided opportunities for exploiting their unique killing properties against tissue-specific tumors. γδ T cells offer relevant advantages over the conventional T cells: they are not MHC-restricted and they serve as a bridge between innate and adaptive immunity. Further manipulation could result improved anti-tumor immunity.

Although there is extensive evidence that γδ T cells have potent anti-tumor activity, early clinical trials involving ex vivo activation and expansion of endogenous Vγ9Vδ2 T cells by pyrophosphates or aminobisphosphonates (N-BP), such as zoledronic acid followed by their adoptive transfer into tumor patients, have shown limited success in tumor control. More studies are needed to address mechanisms of failure of with the aim to improve γδ T immunotherapy. These may involve investigating specific, context-dependent effects of butyrophilins to mediate activation of Vγ9+ γδ T cells which will inform the development of novel molecules that fine tune intracellular signaling in these cells. More recent research efforts have focused on genetic engineering of γδ T cells to express chimeric antigen receptors (CARs) for redirected anti-tumor reactivity, metabolic reprogramming of their intracellular circuitry to overcome tumor-induced immunosuppression and to promote their capacity to galvanize other immune cell types in anti-tumor responses and long-term maintenance following tumor eradication. Innovations to develop platform technologies for the clinical manufacturing γδ T cells are also expected to be important to support these research initiatives.

In this Research Topic, we welcome the submission of Original Research, Review, Methods articles that focus but are not limited to the following subtopics:
• Different approaches to engineer γδ T cells for tumor immunotherapy: CAR; armored to secrete immunomodulatory, anti-tumor cytokines; metabolic programming to enhance anti-tumor function; development of tumor-infiltrating γδ T cells that locally secrete checkpoint blockade mAbs, BiTEs, etc.
• Metabolic programming of γδ T cells to enhance their anti-tumor function.
• Investigation of which subsets of γδ T cells can be activated to optimize anti-tumoral activity: Vγ9+Vδ2+ (blood: new generation phosphoantigens; aminobisphosphonates such as zoledronic acid; synthetic bisphosphonate pro-drug, pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), that both expands Vγ9Vδ2 cells and increases their ability to recognize tumor cells; agonistic anti-BTN3A1 antibodies).
• Vδ1+ γδ T cells expressing various Vγ elements (DOT cells) and other Vδ1/2- [such as Vγ4+Vδ5+ (EPCR as γδ TCR ligand) and Vγ8+Vδ3+ (Annexin A2 as γδ TCR ligand)] γδ T cells, both in circulation and various tissues.
• Contextual factors which determine whether γδ T cells are pro-tumoral or anti-tumoral in others.


Keywords: CAR T cells; cancer immunotherapy; immunosurveillance, γδ T Cell


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

γδ T cells represent an important class of “unconventional” T lymphocytes that play key roles in tumor immunosurveillance. With the increasing recognition of these cells as a clinical correlate for improved disease prognosis, there has been vast interest to harness their unique properties for therapeutic purposes. Seminal studies of Vγ9Vδ2 T cell activation by microbial or endogenous tumor-derived phosphoantigens have set the stage for its applications in targeting tumor. Subsequent discovery of the involvement of butyrophilin/butyrophilin-like proteins in regulating this specific immune reactivity have further paved the way for development of γδ T cell-based therapeutics. Concurrently, advances in understanding the specialized functions of γδ T cell subsets resident in various tissues have provided opportunities for exploiting their unique killing properties against tissue-specific tumors. γδ T cells offer relevant advantages over the conventional T cells: they are not MHC-restricted and they serve as a bridge between innate and adaptive immunity. Further manipulation could result improved anti-tumor immunity.

Although there is extensive evidence that γδ T cells have potent anti-tumor activity, early clinical trials involving ex vivo activation and expansion of endogenous Vγ9Vδ2 T cells by pyrophosphates or aminobisphosphonates (N-BP), such as zoledronic acid followed by their adoptive transfer into tumor patients, have shown limited success in tumor control. More studies are needed to address mechanisms of failure of with the aim to improve γδ T immunotherapy. These may involve investigating specific, context-dependent effects of butyrophilins to mediate activation of Vγ9+ γδ T cells which will inform the development of novel molecules that fine tune intracellular signaling in these cells. More recent research efforts have focused on genetic engineering of γδ T cells to express chimeric antigen receptors (CARs) for redirected anti-tumor reactivity, metabolic reprogramming of their intracellular circuitry to overcome tumor-induced immunosuppression and to promote their capacity to galvanize other immune cell types in anti-tumor responses and long-term maintenance following tumor eradication. Innovations to develop platform technologies for the clinical manufacturing γδ T cells are also expected to be important to support these research initiatives.

In this Research Topic, we welcome the submission of Original Research, Review, Methods articles that focus but are not limited to the following subtopics:
• Different approaches to engineer γδ T cells for tumor immunotherapy: CAR; armored to secrete immunomodulatory, anti-tumor cytokines; metabolic programming to enhance anti-tumor function; development of tumor-infiltrating γδ T cells that locally secrete checkpoint blockade mAbs, BiTEs, etc.
• Metabolic programming of γδ T cells to enhance their anti-tumor function.
• Investigation of which subsets of γδ T cells can be activated to optimize anti-tumoral activity: Vγ9+Vδ2+ (blood: new generation phosphoantigens; aminobisphosphonates such as zoledronic acid; synthetic bisphosphonate pro-drug, pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), that both expands Vγ9Vδ2 cells and increases their ability to recognize tumor cells; agonistic anti-BTN3A1 antibodies).
• Vδ1+ γδ T cells expressing various Vγ elements (DOT cells) and other Vδ1/2- [such as Vγ4+Vδ5+ (EPCR as γδ TCR ligand) and Vγ8+Vδ3+ (Annexin A2 as γδ TCR ligand)] γδ T cells, both in circulation and various tissues.
• Contextual factors which determine whether γδ T cells are pro-tumoral or anti-tumoral in others.


Keywords: CAR T cells; cancer immunotherapy; immunosurveillance, γδ T Cell


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

11 December 2021 Abstract
09 February 2022 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

11 December 2021 Abstract
09 February 2022 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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