Sneaking into the non-conventional niches: Using gamma delta T cells to fight cancer

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Payal Yokota

Despite the advent and access to a variety of targeted immunotherapy approaches, the current paradigm for solid tumors still remains if you can cut it out – you do! Depending on the grade of tumor and degree of metastasis, there’s a substantial risk of tumor resurgence.  In those cases, the best defense against the disease is to be one step ahead. But how can you stay ahead of a disease that stems from within and isn’t hereditary? One way to evade such offense is to engineer therapies that take advantage of tumor weaknesses and coerce a symphony of immunological processes available to its arsenal. In the past few decades, the field of cancer immunotherapy has seen a number of robust strategies that have not only extended the lives of millions of patients but also improved the quality of their lifestyle. As a testament to the current golden era of cancer research, the most recent Nobel Prize in Medicine was awarded to cancer immunotherapy that followed the ceremonious 2017 FDA approval of CAR-T drugs.

The immune system encompasses an organized environment of cell populations that have a variety of roles that encourage defense against diseases. Recent advances in genome-based tools have found new meanings to data collected from patient biopsies and assays conducted with cells grown on a lab dish.  These analyses tell us that the tumor microenvironment (TME) is heterogeneous, relies on continuous energy supply and uses an intricate signaling network to sustain, proliferate and obliterate healthy tissues. In order to systematically fight the tumor growth, immunotherapy takes advantage of a subset of lymphocytes called T cells that circulate through blood, lymph and a variety of tissues in search of target cancer cells. Upon recognition of targets, T cells bind to the signatures on those target cells via receptors they express, get activated and subsequently mount a robust immune response. These and other qualities make immunotherapies based on the redirection of T cells, an effective strategy to fight against tumor growth.  

Recently, two main T cell redirection strategies have been used in the clinic for effective and efficacious anti-cancer responses. The first technique redirects killer T cells by making a chimeric antigen receptor (CAR), receptors engineered like chimeras to target the desired protein for transfer back to the patient. A CAR is engineered such that it has a portion outside the cell that can recognize tumors, then fused with the signaling compartment of a T cell receptor system. This way, when the tumor is recognized, the killing signal is sent out to neutralize the threat.

The second technique redirects T cells by use of engineered proteins that have the capacity of engaging T cells, also known as Bi-specific T cell engagers (or BiTes).  A BiTe is designed such that two recognizing units are connected via linkers such that one targets the cancer cell and the other on the surface of T cells to signal.

In circulating blood of humans, up to 90% of total blood lymphocytes are the conventional αβ T cells, while the other 10% being their counterpart non-conventional γδ T cells. While both these T cell compartments arise from common ancestry, they diverge into distinct compartments early on during their development. This occupational commitment is considered to be non-reversible and remains set throughout our lifetime.  One main difference between the two subsets is that γδ T cells express accessory receptors on their surface that can recognize molecular patterns of foreign invaders as well as damaged self-cells. This unique system gives γδ T cells an advantage to not only act like first responders (as rapid onset innate immune system) but also as recruiters and allies of the αβ T cells (slower-acting adaptive immune system) in blood. Here, we will focus on building strategies that can take advantage of the body’s non-conventional T cells, γδ T cells, in order to fight tumor growth.  To this end, we will briefly discuss the aforementioned T cell redirection technologies in the context of γδ T cell-based immunotherapy, namely γδ CAR-Ts and γδ BiTes.

Schematic of γδ T cell-based CAR-T and BiTe technology. Left Panel shows a γδ T-CAR model where the tumor cell expresses a signature (red) that is recognized by the CAR-T cell (green) via the synthetic unit supported by a hinge and an intracellular signaling domain. Right Panel shows a γδ BiTe model where a tumor recognizing part and T cell engager part are both extracted from specific antibodies and tethered via a linker such that the blue (tumor recognizer) recognizes the tumor and the green (T cell engager) engages for T cell responses.

The first strategy is to use γδ T cell-based CAR-Ts.  In past articles, we have reviewed the specifics of CAR-T therapy, where we talk about modifying T cells isolated from a patient such that they now bear a membrane receptor (Fig 1., Left) that can secrete toxins to neutralize tumors.  In these strategies, T cells from the blood of an individual patient are isolated, upscaled and modified before being re-injected into the patient. Before re-injection, these modified cells are equipped with a synthetic receptor that can engage cytotoxic T cells as well as target tumor cells so as to be more specific and minimize systemic toxicity. Since the γδ T cell receptors have a limited specificity, this attribute can be exploited in engaging γδ CAR-Ts into targeting those tumor signatures that are specific to individual tumors, as well as those lacking on healthy cells.  In addition to selective antitumor cytotoxicity, γδ CARs can also be used as antigen presenting cells to bridge conventional T cell responses. One specific way of engineering γδ CARs is to couple them with sugars and carbohydrates that form patterns on tumor cells distinct from healthy cells.  

A second strategy is to use γδ T cell-based Bispecific T cell engagers (BiTes). Unlike CAR-Ts, BiTes lack the membrane domain of the modified chimeric receptor, rather possess two types of variable fragments from two different antibodies that either engage a T cytotoxic T cell or a target cell (Fig 1., Right). In this system, the linker tethers the two domains together and is used to bind to each cell type it engages. Lack of membrane receptor suggests that BiTes have to be introduced to activated cells and cannot be passed on to subsequent generations as in CAR-Ts. Previous studies have shown that γδ-based T cell engagers significantly reduce leukemia load and enhance tumor targeting (Deniger et al., 2013).  One of the intriguing things about γδ T cells is their ability to recognize antigens that are not peptides and do not require an antigen be presented by macrophages or dendritic cells as in their αβ counterparts. In particular, they are able to recognize salt and ester modified phosphates (pyrophosphates) that are largely expressed on a variety of tumors, and this engagement is able to inhibit specific tumor-associated pathways.

Taken together, from a clinical outlook, use of γδ CAR-Ts or γδ BiTes can expand the current repertoires of tumor-associated antigen recognition as well as provide a robust kill-switch to minimize side effects due to their lack of reactivity to self-peptides. The antigen presentation and regulatory features of γδ T cells can be further coerced to bridge the nonspecific first response and specific adaptive responses when necessary. Therefore, engaging a non-conventional niche rather than a larger T cell repertoire can also decrease, if not eliminate, the systemic stress and inefficient kill-switches that have been known to be a hurdle in current immuno-oncology designs and platforms.

Works discussed:

Slaney et al., 2018. CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment. AACR: Cancer Discovery. 8 (8): p. 924

Capsomidis et al., 2018. Chimeric  Antigen Receptor-Engineered Human Gamma Delta T cells: Enhanced Cytotoxicity with Retention of Cross Presentation. Molecular Therapy. 26 (2): p354.

Deniger et al., 2013. Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous gd T cell receptors and introduced CD19-specific Chimeric Antigen Receptor. Molecular Therapy. 21(3): p638

Art created with Biorender 


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