γδ cell-based immunotherapy for cancer

ABSTRACT

Introduction: Cancer immunotherapy relies on the development of an efficient and long-lasting anti-tumor response, generally mediated by cytotoxic T cells. γδ T cells possess distinctive features that justify their use in cancer immunotherapy.

Areas covered: Here we will review our current knowledge on the functions of human γδ T cells that may be relevant in tumor immunity and the most recent advances in our understanding of how these functions are regulated in the tumor microenvironment. We will also discuss the major achievements and limitations of γδ T cell-based immunotherapy of cancer.

Expert opinion: Several small-scale clinical trials have been conducted in cancer patients using either in vivo activation of γδ T cells or adoptive transfer of ex vivo-expanded γδ T cells. Both strategies are safe and give some clinical benefit to patients, thus providing a proof of principle for their utilization in addition to conventional therapies. However, low objective response rates have been obtained in both settings and therefore larger and well-controlled trials are needed. Discovering the factors which influence the success of γδ T cell-based immunotherapy will lead to a better understanding of their mechanism of action and to harness these cells for effective and durable anti-tumor responses.

KEYWORDS:

• γδ T cells
• cancer
• tumor microenvironment
• adoptive transfer
• cytotoxicity

Article Highlights

• γδ cells area a small subset of T lymphocytes endowed with the capacity to kill a variety of tumor cells in vitro and in pre-clinical cancer models in vivo.

• γδ T cells do not recognize peptides and lack genetic restriction, hence their anti-tumor activity is not affected by downregulation of MHC class I molecules and is especially indicated for tumors with low mutational burdens, which are generally resistant to treatment with checkpoint inhibitors.

• These features have prompted the development of therapeutic strategies in which γδ T cells agonists or ex vivo-expanded γδ T cells have been administered to tumor patients. However, the results of several small-scale phase I-II clinical trials have been inconsistent, given the low objective response rates obtained in both settings.

• It is now firmly established that the tumor microenvironment reprograms tumor-infiltrating γδ T cells to acquire immunosuppressive and tumor-promoting functions, thus explaining the limited success of previous clinical trials.

• The development of innovative strategies (bispecific antibodies and CAR-T) may help to overcome actual limitations and improve the efficacy of γδ T cell-based cancer immunotherapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.