Table Info

Table 1.

A comprehensive list of ongoing oncology clinical trials involving IL-15 in solid tumours

Clinical trial ID	Phase	Number of patients	Cancer type	Treatment	Status	Estimated study completion date
NCT03388632	Phase 1	50	Solid tumour (metastatic or refractory)	Recombinant human IL-15 (rhIL-15) plus nivolumab or ipilimumab	Recruiting	December 2023
NCT05964361	Phase 1/2	10	Oesophageal, pancreatic, ovarian and liver cancer	IL-15-transpresenting Wilms’ Tumor-1 (WT1)-targeted dendritic cell vaccine	Not yet recruiting	September 2025
NCT05304936	Phase 1b/2	60	Advanced pancreatic carcinoma	HCW9218 [bifunctional transforming growth factor β (TGFβ) antagonist/IL-15 protein complex]	Recruiting	February 2025
NCT05620134	Phase 1/2	149	Various unresectable, locally advanced or metastatic tumour types	JK08 (IL-15 antibody fusion protein targeting CTLA-4)	Recruiting	February 2026
NCT05322408	Phase 1	24	Various advanced solid tumours	HCW9218 (bifunctional fusion protein complex of TGFβ receptor II (TGFβRII) domains, human tissue factor, and IL-15, with a second soluble fusion of TGFβRII domains and a domain of IL-15Rα)	Recruiting	January 2027
NCT05470283	Phase 1	30	Metastatic melanoma	OBX-115 [tumour infiltrating lymphocytes (TIL) engineered with membrane-bound IL-15 plus acetazolamide]	Recruiting	April 2027
NCT04294576	Phase 1	92	Locally advanced/metastatic tumours	BJ-001 (IL-15 fusion protein plus pembrolizumab)	Recruiting	October 2024
NCT06060613	Phase 1/2	32	Metastatic melanoma	OBX-115	Recruiting	October 2027
NCT03563157	Phase 1b/2	332	Metastatic CRC	NANT CRC vaccine plus a variety of interventions one of which is ALT-803 (recombinant human super agonist IL-15 complex)	Active	December 2022
NCT05419011	Phase 2	186	Lynch syndrome	Tri-Ad5 vaccines plus nogapendekin alfa (N-803)	Recruiting	February 2027
NCT04390399	Phase 2	328	Pancreatic cancer	Standard-of-care chemotherapy plus aldoxorubicin hydrochloride, N-803 and PD-L1 targeting-high affinity NK (t-haNK)	Recruiting	September 2024
NCT03387085	Phase 1/2	79	Triple-negative breast cancer	NANT triple-negative breast cancer vaccine plus various chemotherapy and immunotherapy agents (one of which is N-803)	Active	October 2023
NCT04290546	Phase 1	25	Squamous cell carcinoma of head and neck, and salivary gland carcinoma	CIML NK cell infusion plus N-803 plus ipilimumab or cetuximab	Recruiting	March 2024
NCT05327530	Phase 2	252	Locally advanced or metastatic urothelial carcinoma	Avelumab plus NKTR-255 (polyethylene glycol-conjugate of rhIL-15)	Recruiting	January 2025
NCT03022825	Phase 2/3	190	High-grade non-muscle invasive bladder cancer	Bacillus Calmette-Guerin (BCG) plus N-803 or N-803 only	Recruiting	October 2028
NCT05445882	Phase 2	28	Castration-resistant prostate cancer	N-803 or N-803 and BN-Brachyury or N-803 and bintrafusp alfa	Not yet recruiting	August 2026
NCT05676749	Phase 1	20	Metastatic NSCLC	C-TIL051 (TIL therapy) plus NKTR-255 plus pembrolizumab	Not yet recruiting	March 2027
NCT04659629	Phase 1	310	Refractory/relapsed solid tumours	NL-201 (IL-2/IL-15 agonist) or NL-201 plus pembrolizumab	Active	December 2024
NCT06083883	Phase 1	44	Synovial sarcoma and myxoid/round cell liposarcoma	NY-ESO-1 T cell receptor (TCR)/IL-15 NK (NK cells engineered to express TCR and IL-15) plus fludarabine plus cyclophosphamide	Not yet recruiting	November 2028
NCT05334329	Phase 1	21	NSCLC	Cord blood (CB)-NK (umbilical CB derived-NK cells) expressing soluble IL-15 (sIL-15) and PD-L1 plus atezolizumab plus fludarabine plus cyclophosphamide	Recruiting	September 2025
NCT06066424	Phase 1	54	Advanced solid tumours	Trophoblast cell surface antigen 2 (TROP2)-chimeric antigen receptor (CAR)-NK cells (IL-15-transduced) plus rimiducid plus fludarabine plus cyclophosphamide	Not yet recruiting	April 2040
NCT04377932	Phase 1	24	Paediatric solid tumours [glypican 3 (GPC3)-positive]	AGAR T cells (GPC3-specific CAR and expresses IL-15)	Recruiting	February 2040
NCT05103631	Phase 1	27	Solid tumours (GPC3-positive)	AGAR T cells	Recruiting	December 2039
NCT05703854	Phase 1/2	50	RCC, mesothelioma and osteosarcoma	CAR.70/IL-15-transduced CB-derived NK cells plus fludarabine plus cyclophosphamide	Recruiting	September 2027
NCT04715191	Phase 1	24	Paediatric solid tumours (GPC3-positive)	CARE T cells (GPC3-specific CAR and expresses IL-15 and IL-21)	Not yet recruiting	August 2041
NCT05922930	Phase 1/2	51	Ovarian cancer and mesonephric-like adenocarcinoma and Pancreatic cancer	TROP2-CAR-NK plus cyclophosphamide plus fludarabine	Not yet recruiting	August 2028
NCT05620342	Phase 1	24	Small and non-small cell lung carcinoma	Inducible caspase 9 (iC9).GD2.CAR.IL-15 T-cells (GD2-specific CAR and expresses IL-15 and iC9)	Recruiting	February 2027
NCT03721068	Phase 1	18	Neuroblastoma and osteosarcoma	iC9.GD2.CAR.IL-15 T-cells plus cyclophosphamide plus fludarabine	Recruiting	June 2039
NCT03294954	Phase 1	36	Neuroblastoma	GINAKIT cells (GD2-specific CAR and expresses IL-15)	Recruiting	August 2040
NCT05642195	Phase 1/2	30	Non-small-cell lung cancer	H1299 lung cancer vaccine with adjuvant alone or plus N-803	Recruiting	December 2035
NCT05396391	Phase 1a/1b/2a	140	Various unresectable solid tumours and refractory non-Hodgkin’s lymphoma*	IAP0971 (immunocytokine that binds specifically to PD-1 and fuses IL-15/IL-15Rα complex)	Recruiting	November 2024
NCT04261439	Phase 1/1b	60	Advanced solid tumours and lymphoma*	NIZ985 (recombinant heterodimer of IL-15 and IL-15Rα plus spartalizumab plus tislelizumab)	Active	November 2023

*: mixed studies where patients with both solid and haematological cancers were included

Declarations

Author contributions

JMV: Formal analysis, Investigation, Validation, Writing—original draft. HFA: Formal analysis, Investigation, Methodology, Writing—original draft. RR: Investigation, Methodology, Validation, Visualization. MB and NC: Investigation, Visualization, Writing—review & editing. EJ: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174:1054–66. [DOI] [PubMed]

Eberl G, Colonna M, Di Santo JP, McKenzie ANJ. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348:aaa6566. [DOI] [PubMed] [PMC]

Walker JA, Barlow JL, McKenzie ANJ. Innate lymphoid cells — how did we miss them? Nat Rev Immunol. 2013;13:75–87. [DOI] [PubMed]

Schuijs MJ, Png S, Richard AC, Tsyben A, Hamm G, Stockis J, et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat Immunol. 2020;21:998–1009. [DOI] [PubMed] [PMC]

Jou E, Rodriguez-Rodriguez N, Ferreira ACF, Jolin HE, Clark PA, Sawmynaden K, et al. An innate IL-25–ILC2–MDSC axis creates a cancer-permissive microenvironment for Apc mutation–driven intestinal tumorigenesis. Sci Immunol. 2022;7:eabn0175. [DOI] [PubMed] [PMC]

Moral JA, Leung J, Rojas LA, Ruan J, Zhao J, Sethna Z, et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature. 2020;579:130–5. [DOI] [PubMed] [PMC]

Liu S, Galat V, Galat Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol. 2021;14:7. [DOI] [PubMed] [PMC]

Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13:145–9. [DOI] [PubMed]

Korchagina AA, Shein SA, Koroleva E, Tumanov AV. Transcriptional control of ILC identity. Front Immunol. 2023;14:1146077. [DOI] [PubMed] [PMC]

10.

Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med. 2014;211:563–77. [DOI] [PubMed] [PMC]

11.

Klose CSN, Flach M, Möhle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014;157:340–56. [DOI] [PubMed]

12.

Asahi T, Abe S, Cui G, Shimba A, Nabekura T, Miyachi H, et al. Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches. Elife. 2023;12:e84209. [DOI] [PubMed] [PMC]

13.

Meininger I, Carrasco A, Rao A, Soini T, Kokkinou E, Mjösberg J. Tissue-specific features of innate lymphoid cells. Trends Immunol. 2020;41:902–17. [DOI] [PubMed]

14.

Zhang J, Le Gras S, Pouxvielh K, Faure F, Fallone L, Kern N, et al. Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells. Nat Commun. 2021;12:5446. [DOI] [PubMed] [PMC]

15.

Zhang J, Marotel M, Fauteux-Daniel S, Mathieu AL, Viel S, Marçais A, et al. T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. Eur J Immunol. 2018;48:738–50. [DOI] [PubMed]

16.

Rodriguez-Rodriguez N, Clark PA, Gogoi M, Ferreira ACF, Kerscher B, Crisp A, et al. Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum. Proc Natl Acad Sci U S A. 2022;119:e2203454119. [DOI] [PubMed] [PMC]

17.

Gasteiger G, Fan X, Dikiy S, Lee SY, Rudensky AY. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015;350:981–5. [DOI] [PubMed] [PMC]

18.

Dutton EE, Gajdasik DW, Willis C, Fiancette R, Bishop EL, Camelo A, et al. Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations. Sci Immunol. 2019;4:eaau8082. [DOI] [PubMed] [PMC]

19.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930–40. [DOI] [PubMed] [PMC]

20.

Li Z, Ma R, Ma S, Tian L, Lu T, Zhang J, et al. ILC1s control leukemia stem cell fate and limit development of AML. Nat Immunol. 2022;23:718–30. Erratum in: Nat Immunol. 2022;23:1286. [DOI] [PubMed] [PMC]

21.

Nixon BG, Chou C, Krishna C, Dadi S, Michel AO, Cornish AE, et al. Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity. Sci Immunol. 2022;7:eabi8642. [DOI] [PubMed] [PMC]

22.

Zhang Y, Ma S, Li T, Tian Y, Zhou H, Wang H, et al. ILC1-derived IFN-γ regulates macrophage activation in colon cancer. Biol Direct. 2023;18:56. Erratum in: Biol Direct. 2023;18:83. [DOI] [PubMed] [PMC]

23.

Dadi S, Chhangawala S, Whitlock BM, Franklin RA, Luo CT, Oh SA, et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell. 2016;164:365–77. [DOI] [PubMed] [PMC]

24.

Ducimetière L, Lucchiari G, Litscher G, Nater M, Heeb L, Nuñez NG, et al. Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc Natl Acad Sci U S A. 2021;118:e2026271118. [DOI] [PubMed] [PMC]

25.

Saul D, Barros LL, Wixom AQ, Gellhaus B, Gibbons HR, Faubion WA, et al. Cell type-specific induction of inflammation-associated genes in Crohn’s disease and colorectal cancer. Int J Mol Sci. 2022;23:3082. [DOI] [PubMed] [PMC]

26.

Luci C, Bihl F, Bourdely P, Khou S, Popa A, Meghraoui-Kheddar A, et al. Cutaneous squamous cell carcinoma development is associated with a temporal infiltration of ILC1 and NK cells with immune dysfunctions. J Invest Dermatol. 2021;141:2369–79. [DOI] [PubMed]

27.

Vienne M, Etiennot M, Escalière B, Galluso J, Spinelli L, Guia S, et al. Type 1 innate lymphoid cells limit the antitumoral immune response. Front Immunol. 2021;12:768989. [DOI] [PubMed] [PMC]

28.

Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–68. [DOI] [PubMed] [PMC]

29.

Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2:e192535. [DOI] [PubMed] [PMC]

30.

Chevalier MF, Trabanelli S, Racle J, Salomé B, Cesson V, Gharbi D, et al. ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence. J Clin Invest. 2017;127:2916–29. [DOI] [PubMed] [PMC]

31.

Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12:21–7. [DOI] [PubMed]

32.

Shih HY, Sciumè G, Poholek AC, Vahedi G, Hirahara K, Villarino AV, et al. Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunol Rev. 2014;261:23–49. [DOI] [PubMed] [PMC]

33.

Martínez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramírez-Alejo N, Mele F, et al. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23. Sci Immunol. 2018;3:eaau6759. [DOI] [PubMed] [PMC]

34.

Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity. 1998;9:669–76. [DOI] [PubMed]

35.

Diefenbach A, Colonna M, Koyasu S. Development, differentiation, and diversity of innate lymphoid cells. Immunity. 2014;41:354–65. [DOI] [PubMed] [PMC]

36.

Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nature Immunol. 2017;18:1004–15. [DOI] [PubMed]

37.

Nabekura T, Shibuya A. Type 1 innate lymphoid cells: soldiers at the front line of immunity. Biomed J. 2021;44:115–22. [DOI] [PubMed] [PMC]

38.

Ma X, Sun J, Papasavvas E, Riemann H, Robertson S, Marshall J, et al. Inhibition of IL-12 production in human monocyte-derived macrophages by TNF. J Immunol. 2000;164:1722–9. [DOI] [PubMed]

39.

Hildreth AD, Padilla ET, Tafti RY, Legala AR, O’Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production. Cell Rep. 2023;42:112141. [DOI] [PubMed] [PMC]

40.

Gotthardt D, Trifinopoulos J, Sexl V, Putz EM. JAK/STAT cytokine signaling at the crossroad of NK cell development and maturation. Front Immunol. 2019;10:2590. [DOI] [PubMed] [PMC]

41.

Yin S, Yu J, Hu B, Lu C, Liu X, Gao X, et al. Runx3 mediates resistance to intracellular bacterial infection by promoting IL12 signaling in group 1 ILC and NCR+ILC3. Front Immunol. 2018;9:2101. [DOI] [PubMed] [PMC]

42.

Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rβ2 expression during human Th1 cell differentiation. EMBO J. 2007;26:1292–302. [DOI] [PubMed] [PMC]

43.

Dulson SJ, Watkins EE, Crossman DK, Harrington LE. STAT4 directs a protective innate lymphoid cell response to gastrointestinal infection. J Immunol. 2019;203:2472–84. [DOI] [PubMed] [PMC]

44.

Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233:6425–40. [DOI] [PubMed]

45.

Qin H, Holdbrooks AT, Liu Y, Reynolds SL, Yanagisawa LL, Benveniste EN. SOCS3 deficiency promotes M1 macrophage polarization and inflammation. J Immunol. 2012;189:3439–48. [DOI] [PubMed] [PMC]

46.

Zhang W, Zhang Y, He Y, Wang X, Fang Q. Lipopolysaccharide mediates time-dependent macrophage M1/M2 polarization through the Tim-3/Galectin-9 signalling pathway. Exp Cell Res. 2019;376:124–32. [DOI] [PubMed]

47.

Pervin M, Karim MR, Kuramochi M, Izawa T, Kuwamura M, Yamate J. Macrophage populations and expression of regulatory inflammatory factors in hepatic macrophage-depleted rat livers under lipopolysaccharide (LPS) treatment. Toxicol Pathol. 2018;46:540–52. [DOI] [PubMed]

48.

Pan Y, Yu Y, Wang X, Zhang T. Tumor-associated macrophages in tumor immunity. Front Immunol. 2020;11:583084. [DOI] [PubMed] [PMC]

49.

Zhang N, Liu C, Jin L, Zhang R, Wang T, Wang Q, et al. Ketogenic diet elicits antitumor properties through inducing oxidative stress, inhibiting MMP-9 expression, and rebalancing M1/M2 tumor-associated macrophage phenotype in a mouse model of colon cancer. J Agric Food Chem. 2020;68:11182–96. [DOI] [PubMed]

50.

Guo H, Zang L, Yang X, Wu Y, Ma J, Shi W. Imbalance of lymphoid cells in peripheral blood maintains the immunosuppression and promotes the development of lung adenocarcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2023;39:729–36. Chinese. [PubMed]

51.

Nabekura T, Riggan L, Hildreth AD, O’Sullivan TE, Shibuya A. Type 1 innate lymphoid cells protect mice from acute liver injury via interferon-γ secretion for upregulating Bcl-xL expression in hepatocytes. Immunity. 2020;52:96–108.e9. [DOI] [PubMed] [PMC]

52.

Wang H, Shen L, Sun X, Liu F, Feng W, Jiang C, et al. Adipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity. Nat Commun. 2019;10:3254. [DOI] [PubMed] [PMC]

53.

Hernández DC, Juelke K, Müller NC, Durek P, Ugursu B, Mashreghi MF, et al. An in vitro platform supports generation of human innate lymphoid cells from CD34⁺ hematopoietic progenitors that recapitulate ex vivo identity. Immunity. 2021;54:2417–32.e5. [DOI] [PubMed]

54.

Jou E. Type 1 and type 2 cytokine-mediated immune orchestration in the tumour microenvironment and their therapeutic potential. Explor Target Antitumor Ther. 2023;4:474–97. [DOI] [PubMed] [PMC]

55.

Cohen J. IL-12 deaths: explanation and a puzzle. Science. 1995;270:908. [DOI] [PubMed]

56.

Kaczanowska S, Beury DW, Gopalan V, Tycko AK, Qin H, Clements ME, et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell. 2021;184:2033–52.e21. [DOI] [PubMed] [PMC]

57.

Zhang L, Davies JS, Serna C, Yu Z, Restifo NP, Rosenberg SA, et al. Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models. J Immunother Cancer. 2020;8:e000210. [DOI] [PubMed] [PMC]

58.

Ortiz-Sánchez E, Helguera G, Daniels TR, Penichet ML. Antibody-cytokine fusion proteins: applications in cancer therapy. Expert Opin Biol Ther. 2008;8:609–32. [DOI] [PubMed] [PMC]

59.

Gout DY, Groen LS, van Egmond M. The present and future of immunocytokines for cancer treatment. Cell Mol Life Sci. 2022;79:509. [DOI] [PubMed] [PMC]

60.

Appelbaum FR, Rowe JM, Radich J, Dick JE. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2001;2001:62–86. [DOI] [PubMed]

61.

Benci JL, Johnson LR, Choa R, Xu Y, Qiu J, Zhou Z, et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell. 2019;178:933–48.e14. [DOI] [PubMed] [PMC]

62.

Ercolano G, Garcia-Garijo A, Salomé B, Gomez-Cadena A, Vanoni G, Mastelic-Gavillet B, et al. Immunosuppressive mediators impair proinflammatory innate lymphoid cell function in human malignant melanoma. Cancer Immunol Res. 2020;8:556–64. [DOI] [PubMed]

63.

Salimi M, Wang R, Yao X, Li X, Wang X, Hu Y, et al. Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer. 2018;18:341. [DOI] [PubMed] [PMC]

64.

Mariotti FR, Quatrini L, Munari E, Vacca P, Moretta L. Innate lymphoid cells: expression of PD-1 and other checkpoints in normal and pathological conditions. Front Immunol. 2019;10:910. [DOI] [PubMed] [PMC]

65.

Ercolano G, Gomez-Cadena A, Dumauthioz N, Vanoni G, Kreutzfeldt M, Wyss T, et al. PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions. Nat Commun. 2021;12:2538. [DOI] [PubMed] [PMC]

66.

Bahhar I, Eş Z, Köse O, Turna A, Günlüoğlu MZ, Çakır A, et al. The IL-25/ILC2 axis promotes lung cancer with a concomitant accumulation of immune-suppressive cells in tumors in humans and mice. Front Immunol. 2023;14:1244437. [DOI] [PubMed] [PMC]

67.

Mlecnik B, Bindea G, Angell HK, Sasso MS, Obenauf AC, Fredriksen T, et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci Transl Med. 2014;6:228ra37. [DOI] [PubMed]

68.

Gao Y, Li W, Wang Z, Zhang C, He Y, Liu X, et al. SEL1L preserves CD8⁺ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis. Cell Mol Immunol. 2023;20:1232–50. [DOI] [PubMed]

69.

Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J. 1995;14:3654–63. [DOI] [PubMed] [PMC]

70.

Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994;13:2822–30. [DOI] [PubMed] [PMC]

71.

Lin JX, Mlgone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, et al. The role of shared receptor motifs and common stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995;2:331–9. [DOI] [PubMed]

72.

Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994;266:1045–7. [DOI] [PubMed]

73.

Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res. 2014;20:2044–50. [DOI] [PubMed] [PMC]

74.

Cimpean M, Keppel MP, Gainullina A, Fan C, Sohn H, Schedler NC, et al. IL-15 priming alters IFN-γ regulation in murine NK cells. J Immunol. 2023;211:1481–93. [DOI] [PubMed]

75.

Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity. 2013;38:769–81. [DOI] [PubMed] [PMC]

76.

Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000;191:771–80. [DOI] [PubMed] [PMC]

77.

Waldmann TA, Dubois S, Miljkovic MD, Conlon KC. IL-15 in the combination immunotherapy of cancer. Front Immunol. 2020;11:868. [DOI] [PubMed] [PMC]

78.

Kansler ER, Dadi S, Krishna C, Nixon BG, Stamatiades EG, Liu M, et al. Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies. Nat Immunol. 2022;23:904–15. Erratum in: Nat Immunol. 2022;23:1285. [DOI] [PubMed] [PMC]

79.

Di Censo C, Marotel M, Mattiola I, Müller L, Scarno G, Pietropaolo G, et al. Granzyme A and CD160 expression delineates ILC1 with graded functions in the mouse liver. Eur J Immunol. 2021;51:2568–75. [DOI] [PubMed] [PMC]

80.

Salomé B, Gomez-Cadena A, Loyon R, Suffiotti M, Salvestrini V, Wyss T, et al. CD56 as a marker of an ILC1-like population with NK cell properties that is functionally impaired in AML. Blood Adv. 2019;3:3674–87. [DOI] [PubMed] [PMC]

81.

Cullen SP, Brunet M, Martin SJ. Granzymes in cancer and immunity. Cell Death Differ. 2010;17:616–23. [DOI] [PubMed]

82.

Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008;26:389–420. [DOI] [PubMed] [PMC]

83.

Aybay E, Elkhalifa M, Akula S, Wernersson S, Hellman L. Two granzyme A/K homologs in Zebra mbuna have different specificities, one classical tryptase and one with chymase activity. Dev Comp Immunol. 2023;148:104920. [DOI] [PubMed]

84.

Kong Q, Xia S, Pan X, Ye K, Li Z, Li H, et al. Alternative splicing of GSDMB modulates killer lymphocyte–triggered pyroptosis. Sci Immunol. 2023;8:eadg3196. [DOI] [PubMed] [PMC]

85.

Kurioka A, Cosgrove C, Simoni Y, van Wilgenburg B, Geremia A, Björkander S, et al. CD161 defines a functionally distinct subset of pro-inflammatory natural killer cells. Front Immunol. 2018;9:486. [DOI] [PubMed] [PMC]

86.

Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27:2278–87. [DOI] [PubMed] [PMC]

87.

Getachew Y, Stout-Delgado H, Miller BC, Thiele DL. Granzyme C supports efficient CTL-mediated killing late in primary alloimmune responses. J Immunol. 2008;181:7810–7. [DOI] [PubMed] [PMC]

88.

Johnson H, Scorrano L, Korsmeyer SJ, Ley TJ. Cell death induced by granzyme C. Blood. 2003;101:3093–101. [DOI] [PubMed]

89.

Chertova E, Bergamaschi C, Chertov O, Sowder R, Bear J, Roser JD, et al. Characterization and favorable in vivo properties of heterodimeric soluble IL-15·IL-15Rα cytokine compared to IL-15 monomer. J Biol Chem. 2013;288:18093–103. [DOI] [PubMed] [PMC]

90.

Wang S, Qu Y, Xia P, Chen Y, Zhu X, Zhang J, et al. Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer. Cell Res. 2020;30:610–22. Erratum in: Cell Res. 2020;30:630. [DOI] [PubMed] [PMC]

91.

Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99. [DOI] [PubMed] [PMC]

92.

Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15:e493–503. [DOI] [PubMed]

93.

Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019;18:121–6. [DOI] [PubMed] [PMC]

94.

Freeman HJ. Colorectal cancer risk in Crohn’s disease. World J Gastroenterol. 2008;14:1810–1. [DOI] [PubMed] [PMC]

95.

Wu Y, Shen J. Innate lymphoid cells in Crohn’s disease. Front Immunol. 2020;11:554880. [DOI] [PubMed] [PMC]

96.

Parronchi P, Romagnani P, Annunziato F, Sampognaro S, Becchio A, Giannarini L, et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am J Pathol. 1997;150:823–32. [PubMed] [PMC]

97.

Coman D, Coales I, Roberts LB, Neves JF. Helper-like type-1 innate lymphoid cells in inflammatory bowel disease. Front Immunol. 2022;13:903688. [DOI] [PubMed] [PMC]

98.

Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, et al. IFN-γ-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide. Blood. 2002;100:1728–33. [PubMed]

99.

Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009;9:361–71. [DOI] [PubMed]

100.

Oshima H, Ishikawa T, Yoshida GJ, Naoi K, Maeda Y, Naka K, et al. TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. Oncogene. 2014;33:3820–9. [DOI] [PubMed]

101.

Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, et al. TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest. 2009;119:2954–64. [DOI] [PubMed] [PMC]

102.

Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. 2018;9:847. [DOI] [PubMed] [PMC]

103.

Rodriguez-Rodriguez N, Gogoi M, McKenzie ANJ. Group 2 innate lymphoid cells: team players in regulating asthma. Annu Rev Immunol. 2021;39:167–98. [DOI] [PubMed] [PMC]

104.

Cella M, Gamini R, Sécca C, Collins PL, Zhao S, Peng V, et al. Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. Nature Immunol. 2019;20:980–91. [DOI] [PubMed] [PMC]

105.

Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M, Yu L, et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat Immunol. 2016;17:626–35. Erratum in: Nat Immunol. 2016;17:1005. [DOI] [PubMed] [PMC]

106.

Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM, Golebski K, et al. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol. 2016;17:636–45. [DOI] [PubMed]

107.

Lim AI, Menegatti S, Bustamante J, Le Bourhis L, Allez M, Rogge L, et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J Exp Med. 2016;213:569–83. [DOI] [PubMed] [PMC]

108.

Heinrich B, Gertz EM, Schäffer AA, Craig A, Ruf B, Subramanyam V, et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut. 2022;71:1161–75. [DOI] [PubMed] [PMC]

109.

Bruno A, Focaccetti C, Pagani A, Imperatori AS, Spagnoletti M, Rotolo N, et al. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia. 2013;15:133–42. [DOI] [PubMed] [PMC]

110.

Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14:55. [DOI] [PubMed] [PMC]

111.

Koh J, Kim HY, Lee Y, Park IK, Kang CH, Kim YT, et al. IL23-producing human lung cancer cells promote tumor growth via conversion of innate lymphoid cell 1 (ILC1) into ILC3. Clin Cancer Res. 2019;25:4026–37. [DOI] [PubMed]

112.

Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345–8. [DOI] [PubMed] [PMC]

113.

Ma S, Cheng Q, Cai Y, Gong H, Wu Y, Yu X, et al. IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 2014;74:1969–82. [DOI] [PubMed]

114.

Liu Y, Song Y, Lin D, Lei L, Mei Y, Jin Z, et al. NCR⁻ group 3 innate lymphoid cells orchestrate IL-23/IL-17 axis to promote hepatocellular carcinoma development. EBioMedicine. 2019;41:333–44. [DOI] [PubMed] [PMC]

115.

Sainson RCA, Johnston DA, Chu HC, Holderfield MT, Nakatsu MN, Crampton SP, et al. TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood. 2008;111:4997–5007. [DOI] [PubMed] [PMC]

116.

Castleman MJ, Dillon SM, Purba C, Cogswell AC, McCarter M, Barker E, et al. Enteric bacteria induce IFNγ and granzyme B from human colonic group 1 innate lymphoid cells. Gut Microbes. 2020;12:1667723. [DOI] [PubMed] [PMC]

117.

Mirlekar B, Pylayeva-Gupta Y. IL-12 family cytokines in cancer and immunotherapy. Cancers (Basel). 2021;13:167. [DOI] [PubMed] [PMC]

118.

Cortez VS, Ulland TK, Cervantes-Barragan L, Bando JK, Robinette ML, Wang Q, et al. SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling. Nat Immunol. 2017;18:995–1003. [DOI] [PubMed] [PMC]

119.

Chauvin J, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8:e000957. [DOI] [PubMed] [PMC]

120.

Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015;517:386–90. Erratum in: Nature. 2016;536:359. [DOI] [PubMed] [PMC]

121.

Sivori S, Pende D, Quatrini L, Pietra G, Della Chiesa M, Vacca P, et al. NK cells and ILCs in tumor immunotherapy. Mol Aspects Med. 2021;80:100870. [DOI] [PubMed]

122.

Fionda C, Scarno G, Stabile H, Molfetta R, Di Censo C, Gismondi A, et al. NK cells and other cytotoxic innate lymphocytes in colorectal cancer progression and metastasis. Int J Mol Sci. 2022;23:7859. [DOI] [PubMed] [PMC]

123.

Sanchez-Correa B, Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Bergua JM, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE axis: novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers (Basel). 2019;11:877. [DOI] [PubMed] [PMC]

124.

He LX, Yang L, Liu T, Li YN, Huang TX, Zhang LL, et al. Group 3 innate lymphoid cells secret neutrophil chemoattractants and are insensitive to glucocorticoid via aberrant GR phosphorylation. Respir Res. 2023;24:90. [DOI] [PubMed] [PMC]