unveiling-therapeutic-opportunities-with-melanoma-patient-derived

Unveiling Therapeutic Opportunities with Melanoma Patient-derived Organoid Models

With the development of immunotherapy, there is an ongoing need to develop models that can recapitulate the tumor microenvironment of native tumors. While ...

University of Pennsylvania

Gamma-delta (γδ) T lymphocytes are primed to potently respond to pathogens and transformed cells by recognizing a broad range of antigens. However, adoptive immunotherapy with γδT cells has exhibited mixed treatment responses. Better understanding of γδT cell biology and stratifying healthy donors for allogeneic adoptive therapy is clinically needed to fully realize the therapeutic potential of γδT cells.

Dichotomous and stable gamma delta T-cell number and function in healthy individuals.

Small extracellular vesicles (sEVs) are extracellular nanovesicles that contain bioactive proteins, lipids, RNA, and DNA. A variety of biological process is regulated with sEVs. sEVs are an intercellular messenger regulating recipient cell function and play a role in disease initiation and progression. sEVs derived from certain cells, such as mesenchymal stem cells and immune cells, have the potential for clinical therapy as they possess the characteristics of their parental cells. With better understanding of sEVs biogenesis, their transportation properties, extended circulatory capability, and exceptional biocompatibility, sEVs emerge as a potential therapeutic tool in the clinic. Here, we summarize applications of sEVs-based therapies in different diseases and current knowledge about the strategies in bioengineered sEVs, as well as the challenges for their use in clinical settings.

Small extracellular vesicles-based cell-free strategies for therapy.

Regulatory T cells (Tregs) are essential in the maintenance of immunity, and they are also a key to immune suppressive microenvironment in solid tumors. Many studies have revealed the biology of Tregs in various human pathologies. Here we review recent understandings of the immunophenotypes and suppressive functions of Tregs in melanoma, including Treg recruitment and expansion in a tumor. Tregs are frequently accumulated in melanoma and the ratio of CD8 T cells versus Tregs in the melanoma is predictive for patient survival. Hence, depletion of Tregs is a promising strategy for the enhancement of anti-melanoma immunity. Many recent studies are aimed to target Tregs in melanoma. Distinguishing Tregs from other immune cells and understanding the function of different subsets of Tregs may contribute to better therapeutic efficacy. Depletion of functional Tregs from the tumor microenvironment has been tested to induce clinically relevant immune responses against melanomas. However, the lack of Treg specific therapeutic antibodies or Treg specific depleting strategies is a big hurdle that is yet to be overcome. Additional studies to fine-tune currently available therapies and more agents that specifically and selectively target tumor infiltrating Tregs in melanoma are urgently needed.

Targeting regulatory T cells for immunotherapy in melanoma.

Gamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy.

Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function.

Gamma delta (γδ) T lymphocytes are promising candidate for adoptive T cell therapy, however, their treatment efficacy is not satisfactory. Vδ2 T cells are unique to primates and few suitable models are available to assay their anti-tumour function.

Preclinical platforms to study therapeutic efficacy of human γδ T cells.

Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy.

Article	Year
Dichotomous and stable gamma delta T-cell number and function in healthy individuals. Journal for immunotherapy of cancer\| PubMed ID: 34011536	2021
Small extracellular vesicles-based cell-free strategies for therapy. MedComm\| PubMed ID: 34766134	2021
Targeting regulatory T cells for immunotherapy in melanoma. Molecular biomedicine\| PubMed ID: 34806028	2021
Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function. Journal for immunotherapy of cancer\| PubMed ID: 34937742	2021
Preclinical platforms to study therapeutic efficacy of human γδ T cells. Clinical and translational medicine\| PubMed ID: 35731974	2022
Patient-derived melanoma organoid models facilitate the assessment of immunotherapies. EBioMedicine\| PubMed ID: 37229906	2023

Lingling Ou

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