Tipping the Balance: Could ILCs Be Used for Cancer Immunotherapy?

Cancer cells are able to multiply and spread in the body via their ability to dodge or quell the attacks mounted by the immune system against them. Therefore, it’s no surprise that an area of cancer treatment has emerged that aims to bolster the immune response, arming it with the abilities needed to destroy enemy cells.

Typically, T cells are targeted for immunotherapy, in particular, with treatments such as immune checkpoint inhibitors, which block the inhibitory signals bestowed on T cells by cancer cells, enabling their reinvigoration (Want et al. 2023). But why should T cells have all the fun? Many patients fail to respond to such treatments, thus, the need to expand immunotherapy approaches persists, and now researchers have begun looking at other immune cells to pursue.

In this blog, we discuss the role of innate lymphoid cells (ILCs) in cancer and their potential as therapeutic targets.

What Are ILCs?

ILCs are a group of cells that derive from the common lymphoid progenitor (CLP) and share fundamental transcription factors (TFs) and functions with T cells but lack antigen-specific receptors. The group consists of five subsets: ILC1s, ILC2s, ILC3s, natural killer (NK) cells, and lymphoid-tissue inducer (LTi) cells (Eberl et al. 2015). 

Due to their similarity, ILCs are often thought of as the innate counterparts of specific T cell subsets. ILC1s mirror CD4+ T helper (Th) type 1 (Th1) cells, with both producing interferon-y (IFNy) and expressing the TF T-bet, while ILC2s express GATA3 and produce interleukin (IL)-5 and IL-13 reflecting Th2 cells, and ILC3s express RORyt and produce IL-17 and IL-22 echoing Th17 cells. NK cells, on the other hand, display parallel actions to cytotoxic CD8+ T cells (Nabekura and Shibuya 2021, Robinette and Colonna 2017). Lastly, LTi cells are thought to be a subtype of ILC3 that function predominantly in the development of secondary lymphoid organs in embryogenesis (Zhong et al. 2019).

One of the main differences between ILCs and T cells is their circulation. While naïve T cells constantly migrate throughout the body in search of their cognate antigen, ILCs remain local and are predominantly tissue-resident. For this reason, ILCs are thought to play a role in maintaining tissue homeostasis in the steady state and facilitating tissue repair following injury (Cherrier et al. 2020).

ILCs in Cancer: Walking a Tightrope

So, now that we know the basics of ILCs, how do they relate to cancer? Do they promote or suppress cancer pathogenesis? Well, as with most aspects of science, it’s not quite that simple. ILCs can have both protumor and antitumor properties, depending largely upon their phenotype, the type of cancer, and the tumor microenvironment (TME).

The TME describes the tumor ecosystem, including cancer cells, infiltrating immune cells, stromal cells, and the extracellular matrix (ECM). The TME is crucial to the growth and sustenance of the tumor, so understanding the intricacies of this niche could be valuable for developing new treatment options.

ILCs can rapidly respond to triggers to shape the tissue microenvironment. For example, IFNy secreted by NK cells has been shown to increase fibronectin 1 (FN1) expression on tumor cells, which in turn causes structural changes to the ECM, resulting in decreased metastasis (Glasner et al. 2018).

Conversely, in non-small-cell lung carcinoma (NSCLC), melanoma, breast, and colon cancer, a specific subset of NK cells in the tumor has displayed increased production of vascular endothelial growth factor (VEGF), a pro-angiogenic factor that increases the formation of new blood vessels and supports tumor growth (An et al. 2020).

ILC2s also have a complicated relationship with tumors. Via the production of IL-13, ILC2s have been shown to recruit myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which dampen the antitumor response and are associated with poor survival rates in different forms of cancer, such as bladder cancer and NSCLC (Bahhar et al. 2023, Chevalier et al. 2017).

However, ILC2s have also been reported to recruit dendritic cells, supporting the priming and activation of antigen-specific cytotoxic T cells, in an effort that promotes antitumor defense mechanisms (Wen et al. 2023).

Pretty confusing, right? And this isn’t an exhaustive list. A plethora of additional studies exist that investigate the conflicting mechanisms of ILCs in cancer. Put simply, ILCs walk a fine line between good and bad, and to benefit from this delicate balance, we need to know how to manipulate them to get the outcome we want.

ILCs in Immunotherapy: The Redemption Arc?

So, when it comes to targeting ILCs for immunotherapy, where do we even begin? Well, given their potent tumor-killing capacity, scientists have already started to develop and test the efficacy of different NK cell-mediated therapies. Adoptive NK cell therapies, in which pre-activated NK cells are transferred into a patient, have been found to be well-tolerated and show fewer side effects than adoptive T cell therapies (Jacquelot et al., 2022).

However, the effects of adoptive NK cell therapy in cancer trials have been modest, and so, researchers have begun to explore combination therapies. For example, Cichocki et al. (2023) cultured NK cells ex vivo with IL-15 and nicotinamide to enhance their cytotoxicity and cytokine production and transferred them to patients with relapsed or refractory non-Hodgkin lymphoma and multiple myeloma, in combination with monoclonal antibody therapy. They observed that out of 19 total patients, there was an overall response rate of 74%, with 13 patients having a complete response and one with a partial response.

Whenever it comes to manipulating the other ILC subsets, however, the direction is far less clear.

One study by Munneke et al. (2014) characterized the ILC reconstitution after hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia. HSCT is a treatment widely used in disorders of hematopoietic cells in which the patient's blood cells are eradicated, often using chemotherapy, and replaced with donor stem cells to reset and replenish the immune system with healthy cells. Whilst effective, HSCT therapy can be complicated by graft-versus-host-disease (GVHD). The researchers found that the presence of a subset of ILCs, namely the natural cytotoxicity receptor positive (NCR+) ILC3s, was correlated with a decreased incidence of GVHD. This indicated a protective effect of these cells and suggested that supplementing patients with these cells could have potential advantages (Munneke et al. 2014).

In general, our ability to differentiate between “good” and “bad” ILC subsets in cancer is still extremely limited. So, while there is potential to target ILCs for cancer immunotherapy, more research is nevertheless needed to see the full spectrum of possible benefits.