Table 1.

ILC phenotypes, functions and clinical correlations in different tumors

ILC type	Tumor type	Phenotype	Clinical status/tumor progression	Function/mechanism	Organism	References
ILC1	CLL	Lin−CRTH2–CD117−	Poor clinical outcome	Impaired function due to disturbed TNF‐α production.	Human	[13]
	AML	Lin–CD127+ T‐bet+	Poor clinical outcome	Impaired in the production of IFN‐γ or type 2 cytokines.	Human	[14]
		CD16−CD127+c‐Kit−CRTH2−CD56+	Poor clinical outcome	Impaired cytotoxicity; the cytotoxicity of this subset is regulated by TRAIL, NKp30, NKp80, NKG2A and is KIR independent; TGF‐β1 and AhR ligands might impair their cytotoxicity in AML.	Human	[15]
	NSCLC	CD45+Lin−c‐kit−CRTH2− CD127+CD56−T‐bet+Eomeslo	Associated with tumor progression both in human and mice	The cytotoxicity of this subset is positively associated with Eomes expression; impaired cytotoxicity due to less IFN‐γ production.	Human and mice	[40]
	Breast Cancer	TCR−NK1.1+CD49ahi	Inhibited tumor growth	Expresses high levels of GzmB, GzmC, and TRAIL and exhibit cytotoxicity towards tumor cells; constitutive IL‐15 overexpression is able to expand this subset.	Mice	[16]
	Melanoma	CD49a+CD49b−Eomesint	Unable to control local tumor growth and metastasis	Expresses higher level inhibitory immunological checkpoint receptors, such as CTLA‐4, CD96 and LAG‐3, and produces more myeloid growth factor GM‐CSF and TNF compared to tumor NK cells; TGF‐β drives the conversion of NK cells into ILC1s.	Mice	[67]
	CRC	Lin−CD45+CD127+NK1.1+NKp46+	NA	ILC1s expresses high levels of activating receptors (Klrd1, Ncr1, Klrc2, Klrb1c), and inhibitory receptors (Klre1, Klra7) at the early and late stage of CRC, respectively, while the production of IFN‐γ in ILC1s from late stage of CRC is remarkably decreased.	Mice	[41]
ILC2	APL	Lin−CD127+CRTH2+cKit−/+	Increases in the PBMC of APL patients; associated with increased APL mice mortality.	ILC2s are increased and hyperactivated through the interaction of CRTH2 and NKp30 with elevated tumor‐derived PGD2 and B7H6, respectively; in turn, ILC2s activates M‐MDSCs via producing IL‐13.	Human and mice	[60]
	MM	Lin–CD127+CD25+KLRG1hi	Have no effect on the growth and dissemination of myeloma cells	IL‐33‐inducing circulating KLRG1hi ILC2s inhibits protective type 1 immune responses against MM.	Mice	[43]
	Metastatic lung cancer	Lin−ST2+CD127+CD90.2+	Lacking of ILC2s associated with tumor growth and metastasis	IL‐33 induces ILC2s accumulation in tumor, which in turn mediate tumor immune‐surveillance by cooperating with DCs to promote adaptive cytolytic T‐cell responses.	Mice	[49]
	LLC	ICOS+ST+	Promotes tumor growth	Enhances the type II cytokine levels; increases AMM.	Mice	[63]
	Melanoma	CD11b−CD11c−NK1.1+FcεRI+ CD25+CD45+CD90.2+	Promotes tumor growth	IL‐33 promoted the expansion of ILC2s, which in turn inhibited NK activation and cytotoxicity through expressing the immunosuppressive ectoenzyme CD73.	Mice	[69]
		CD45+CD3–B220–NK1.1–Lin–CD127+RORγt–GATA3+	Promotes lung metastases and mortality	IL‐33‐denpendent ILC2s activation suppresses the production of IFN‐γ and cytotoxicity of lung NK cells, which might be reliant on IL‐5‐induced lung eosinophilia.	Mice	[70]
	PDAC	CD25+CD127+ST2+ GATA3+	Correlated with longer survival in PDAC patients; ILC2s inhibits pancreas‐specific tumor growth in PDAC mice.	IL‐33 induces ILC2s activation to prime CD8+ T cells; ILC2s stimulates tissue‐specific cancer immunity by recruiting intratumoral dendritic cells and partially contribute to the efficacy of PD‐1 pathway blockade.	Human and mice	[58]
	Gastric Cancer	Lin−ICOS+IL‐17RB+	Increased frequency in patients with gastric cancer.	Contributes to immunosuppressive microenvironment and closely related to the upregulation of MDSCs and M2 macrophages in gastric patients.	Human	[71]
	Breast Cancer	Lin−Sca‐1+ST+	Promotes breast cancer progression	IL‐33 induces ILC2s activation, which might influence immunosuppressive functionality of MDSCs through producing IL‐13.	Mice	[65]
		CD45+Lin−CD56−CD127+CRTH2+cKit +/−	Enriched in human breast cancer tissue	ILC2s highly expressed PD‐1 in comparison to circulating ILCs in peripheral blood.	Human	[64]
	NMIBC	Lin−CD127+CRTH2+	Poor clinical outcome	ILC2s recruits immunosuppressive cells, including M‐MDSCs and monocytes, through producing IL‐13, especially in the presence of BCG or tumor cells.	Human	[83]
	CCA	Lin−ST2+	Promote cholangiocyte hyperplasia and cholangiocarcinoma with liver metastases	Releases high levels of IL‐13 that promotes cholangiocyte hyperplasia; IL‐33/ILC2/IL‐13 circuit associated with constitutive activation of AKT and YAP in bile ducts lead to cholangiocarcinoma with liver metastases.	Mice	[72]
	CRC	Lin−CD45+CD127+ST2+KLRG1+PD1high	Promotes tumor growth	Expresses high levels of PD‐1 and HS3ST1; deletion PD‐1 or HS3ST1 suppressed tumor development and proliferation.	Mice	[41]
ILC3	NSCLC	Lin− CD127+CD117+NKp44+	Accumulates in stage I/II NSCLC than in more advanced tumor stages and correlates with the density of intratumoral tertiary lymphoid structures.	Produces IL‐22, TNF‐α, IL‐8, and IL‐2, and activates endothelial cells; recognize lung tumor cells via NKp44; possesses lymphoid tissue inducing properties.	Human	[50]
	SqCC	CD3−CD117+RORγt+	Associated with short survival of patients with SqCC	Promotes IL17‐mediated tumor cell proliferation.	Human	[62]
	Melanoma	NKp46+RORγt+	Represses subcutaneous tumor growth	Induces upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte infiltration.	Mice	[52]
	Breast cancer	CD3−CD11c−B220−CD127+CD90.2+NKp46−	Correlates with lymphatic tumor cell invasion and draining LN metastasis	Stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3‐stromal interactions and production of the cancer cell motile factor RANKL.	Human and mice	[66]
	PC	Lin–CD127+CRTH2–c‐Kit+ NKp44+	Correlates with tumor distant metastasis and vascular invasion in PC patients	Promotes the proliferation, invasion, and migration of PC cell lines by secreting IL‐22 to activate AKT signaling	Human	[75]
	CRC	B220−CD3−NK1.1−CD45+CD90.2+ RORγt+	Promotes tumor growth	Reduced IL‐22 production in ILC2s in Card9 deficient mice.	Mice	[81]
		Lin−CD45+CD127+RORγt−	Promotes tumor growth	ILC3s transdifferentiate into IL‐10‐producing ILCregs during CRC progression in the presence of TGF‐β.	Mice	[41]

ALCL, anaplastic large cell lymphoma; AHR, aryl hydrocarbon receptor; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CCA, Cholangiocarcinoma; CRC, colorectal cancer; DC, dendritic cell HCC, hepatocellular carcinoma; ILCregs, regulatory innate lymphoid cells; LLC, Lewis lung cancer; LN, lymph node; MDSCs, myeloid‐derived suppressor cells; MM, multiple myeloma; NA, not available; NK, natural killer cell; NMIBC, non‐muscle–invasive bladder cancer; NSCLC, non‐small cell lung cancer; PBMC, peripheral blood mononuclear cells; PC, pancreatic cancer; PDAC, pancreatic ductal adenocarcinoma; SqCC, Squamous Cell Carcinomas; ST2, IL‐33 receptor. TME, tumor microenvironment;