Immunotherapies targeting conventional T cells have revolutionized systemic treatment for many cancers, yet only a subset of patients benefit from these approaches. A better understanding of the complex immune microenvironment of tumours is needed to design the next generation of immunotherapeutics. Innate lymphoid cells (ILCs) and innate-like T cells (ILTCs) are abundant, tissue-resident lymphocytes that have recently been shown to have critical roles in many types of cancers. ILCs and ILTCs rapidly respond to changes in their surrounding environment and act as the first responders to bridge innate and adaptive immunity. This places ILCs and ILTCs as pivotal orchestrators of the final antitumour immune response. In this Review, we outline hallmarks of ILCs and ILTCs and discuss their emerging role in antitumour immunity, as well as the pathophysiological adaptations leading to their pro-tumorigenic function. We explore the pleiotropic, in parts redundant and sometimes opposing, mechanisms that underlie the delicate interplay between the different subsets of ILCs and ILTCs. Finally, we highlight their role in amplifying and complementing conventional T cell functions and summarize immunotherapeutic strategies for targeting ILCs and ILTCs in cancer.
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The authors thank J. Zhu (NIH) for critical reading of the manuscript and helpful suggestions and comments. The authors apologize to all the scientists whose work could not be cited owing to space limitations. B.R. was supported by the International Liver Cancer Association Fellowship Award 2021. T.F.G. was supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011345).
The authors declare no competing interests.
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- αβ T cells
T cells expressing a lineage-specific heterodimeric T cell receptor consisting of an α-chain and a β-chain (as opposed to γδ T cell receptors).
- Antibody opsonization
Antigen-specific antibodies can bind to foreign pathogens or transformed cells and mark them for elimination by phagocyting cells.
- Degrees of innateness
This term was previously coined, for example, by Gutierrez-Arcelus et al.10 and Constantinides and Belkaid11, to describe where an immune response lies on the continuum that exists between innate and adaptive immunity.
- Graft-versus-host disease
(GvHD). A potentially fatal complication after allogeneic cell transfer caused by a detrimental reaction of the transferred allogeneic T cells (graft) against the (host) healthy tissue of the recipient.
- Lymphoid tissue-inducing (LTi) cells
These cells are members of the innate lymphoid cell family that promote generation of secondary lymphoid structures.
- M2 macrophages
Although defining macrophage polarization is oversimplistic, this is commonly used to describe alternatively activated macrophages with immunosuppressive features that are often associated with poor outcomes in cancer.
- ‘Missing-self’ mechanism
This describes a mechanism of nature killer cell activation, in which absence or altered expression of major histocompatibility complex I molecules (for example, on tumour cells) leads to the recognition and elimination of these target cells.
- Pancreatic intraepithelial neoplasia
A precursor lesion to invasive ductal adenocarcinoma of the pancreas with well-defined histological features.
An inflammatory pathway leading to cell death as mediated by activation of caspase 1 and inflammatory cytokines such as IL-1β and IL-18.
The transcription factor T-bet (encoded by TBX21) promotes the differentiation programmes of innate and adaptive lymphocytes towards interferon-γ-producing type 1 cells.
- Toll-like receptor
Pattern-recognition receptor expressed on innate immune cells that recognizes structurally conserved molecules (also called pathogen-associated molecular patterns) derived from microorganisms.
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Ruf, B., Greten, T.F. & Korangy, F. Innate lymphoid cells and innate-like T cells in cancer — at the crossroads of innate and adaptive immunity. Nat Rev Cancer 23, 351–371 (2023). https://doi.org/10.1038/s41568-023-00562-w