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Effect of PD1/PDL1 on the Anti-tumor Effects of γδ T Cells
Online InquiryIn recent years, immune checkpoint inhibitors have become a hot trend in tumor treatment and research, and a wide variety of immune checkpoint inhibitors have been introduced into the clinic. Immune checkpoint inhibitors have become the most promising way to treat tumors. In the past, it was generally believed that the function of immune checkpoint inhibitors such as anti-PD1 antibodies was to increase the anti-tumor ability of αβ T cells by inhibiting the depletion of T cells.
However, recent studies have found that the immune checkpoint PD1 can deplete cytotoxic T cells but at the same time allow non-depleted T cells to survive and proliferate because of the presence of PD1. This is a bit of a contradiction, so some researchers are wondering if the PD1 inhibitors actually work on other types of T cells such as γδ T cells.
In this paper, Creative Biolabs explores how PD1/PDL1 regulation affects the anti-tumor effects of γδ T cells and the therapeutic implications of these insights.
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| γδ TCR-Ligand Reaction Analysis Services | Attempts have been made to discover and characterize more possible γδ TCR ligands in order to elucidate the functional mechanisms of γδ T cells. Creative Biolabs offers a comprehensive γδ TCR ligand interaction analysis service that includes a range of methods to characterize and analyze the γδ TCR-ligand response. |
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| γδ T Cells Combined with Immune Checkpoint Inhibitors | Our scientists are interested in the study of immune checkpoint inhibitors and γδ T cells. Our goal is to provide our global clients with the most specialized service by combining these two powerful tools. |
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Anti-tumor Effects of γδ T Cells in Anti-PD1/PDL1 Antibodies
In order to verify the anti-tumor effects of γδ T cells in anti-PD1/PDL1 antibodies, a study was conducted by researchers. The study divided melanoma patients into two groups, one group of patients who did not respond in anti-PD1 & anti-PDL1 antibody treatment and one group of patients who responded. It was found that the expression of the TRDV1 gene (which is the gene that characterizes γδ T cells) was associated with efficacy.
- Patients in the non-responder group had a significantly lower TRDV1 gene and a significantly shorter progression-free survival time than those who responded.
- Moreover, this finding was more pronounced in patients with low tumor mutational load.
Because γδ T cells are not required to recognize antigenic peptides via MHC, unlike αβ T cells, this finding reinforces the importance of γδ T cells in anti-PD1 and PDL1 antibodies.
Impact of PD1/PDL1 Modulation on γδ T Cell Anti-tumor Responses
The influence of PD1/PDL1 signaling on γδ T cell-mediated anti-tumor responses is a subject of ongoing investigation, with findings pointing towards a complex interplay between immune activation and suppression within the TME. Understanding how PD1/PDL1 modulation affects γδ T cell functions is crucial for devising effective immunotherapeutic strategies. Here, we elucidate the diverse mechanisms through which PD1/PDL1 interactions shape γδ T cell responses in the tumor milieu.
Fig. 1 PD-1 controls the IL-17A-producing γδ T cell subset in cancer.1
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Regulation of γδ T Cell Activation and Effector Functions
PD1/PDL1 engagement can modulate γδ T cell activation and effector functions, impacting their cytotoxicity, cytokine production, and antigen recognition capabilities. While PD1 signaling may attenuate γδ T cell responses under certain conditions, it can also fine-tune their activities to prevent excessive inflammation and tissue damage within the TME. -
Modulation of γδ T Cell Trafficking and Localization
The expression of PD1 and PDL1 on tumor and stromal cells influences γδ T cell trafficking and localization within the TME. PD1/PDL1 interactions may regulate the infiltration of γδ T cells into tumors, their retention within specific niches, and their interactions with other immune and stromal components, thereby shaping the spatial dynamics of anti-tumor immunity. -
Induction of Immune Tolerance and Exhaustion
Persistent PD1/PDL1 signaling can lead to the exhaustion and dysfunction of γδ T cells, impairing their anti-tumor effector functions. Prolonged exposure to PDL1-expressing tumor cells may induce anergy or exhaustion in γδ T cells, rendering them less responsive to antigen stimulation and immunotherapeutic interventions. -
Crosstalk with Other Immune Cell Populations
The PD1/PDL1 axis influences the crosstalk between γδ T cells and other immune cell populations within the TME, including αβ T cells, NK cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs). Modulation of PD1/PDL1 signaling can alter the balance of immune cell interactions, shaping the overall anti-tumor immune response and therapeutic outcomes.
Therapeutic Implications and Future Directions
The intricate interplay between PD1/PDL1 signaling and γδ T cell-mediated anti-tumor responses presents both challenges and opportunities for cancer immunotherapy. Harnessing the therapeutic potential of this interaction requires a comprehensive understanding of the underlying mechanisms and careful consideration of the complexities involved. Several therapeutic strategies aimed at manipulating the PD1/PDL1 axis and enhancing γδ T cell-mediated tumor immunity are currently under investigation, including:
| Therapeutic Strategies | Specific Programs |
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| Checkpoint Inhibitor Therapy | Immune checkpoint inhibitors targeting PD1 or PDL1 have transformed cancer therapy by unleashing T cell-mediated anti-tumor responses. Investigating their efficacy in enhancing γδ T cell responses and overcoming immune evasion mechanisms within the TME is an active therapeutic area. |
| Combination Immunotherapy | Combinatorial approaches that target multiple immune checkpoints or modulate different components of the immune system are expected to enhance γδ T-cell-mediated tumor immunity. Strategies combining PD1/PDL1 blockade with γδ T-cell-targeted therapies, cytokine therapies, or other immunomodulators may be able to synergistically enhance anti-tumor immune responses. |
| γδ T Cells Engineering | Genetic engineering techniques such as CAR γδ T-cell therapy can precisely manipulate γδ T-cell function and antigen specificity. By integrating PD1/PDL1-resistant γδ T cells or modifying their TCR signaling pathway, researchers seek to enhance the durability, cytotoxicity, and tumor-targeting capabilities of γδ T cell-based therapies. |
| Targeting Tumor-promoting Pathways | In addition to directly targeting the PD1/PDL1, therapeutic interventions aimed at disrupting tumor-promoting pathways and immunosuppressive mechanisms within the TME may indirectly enhance γδ T cell-mediated anti-tumor immunity. Strategies targeting regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and other immunosuppressive cell populations aim to create a more permissive immune microenvironment for γδ T cell activation and function. |
The intricate interplay between PD1/PDL1 signaling and γδ T cell-mediated anti-tumor responses underscores the complexity of the immune landscape within the TME. Deciphering the mechanisms of this interaction and its impact on tumor immunity is critical for designing effective immunotherapeutic strategies. Creative Biolabs aims to shed light on ongoing research efforts to advance innovative γδ T cell therapies.
Reference
- Edwards, Sarah C., et al. "PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A–producing γδ T cells." Journal of Experimental Medicine 220.2 (2023).
