IL23-Producing Human Lung Cancer Cells Promote Tumor Growth via Conversion of Innate Lymphoid Cell 1 (ILC1) into ILC3

Abstract

Purpose: The plasticity of innate lymphoid cells (ILCs) has been reported in vitro and in the microenvironment of the intestine. However, whether ILC plasticity contributes to regulation of the tumor microenvironment remains unknown. In this study, we explored plasticity of ILCs in human lung cancer. Experimental Design: We analyzed immune subsets and cytokine expression in lung cancers freshly obtained from 80 patients and explored conversion of ILC1 into ILC3 in coculture with lung cancer cells. Prognostic effects of converted ILC3 and related pathway were evaluated by retrospective cohort composed of 875 patients with lung cancer. Results: Low percentages of ILC1, and high percentages of ILC3 were found in pulmonary squamous cell carcinomas (SqCC) but not adenocarcinomas (ADC). In non-small-cell lung cancers, the percentage of ILC3 was associated with IL23 expression in tumor cells but not immune cells. In cocultures, tumor cells of SqCCs converted ILC1 into ILC3 by producing IL23, thus promoting IL17-mediated tumor cell proliferation. Consistently, among IL17 þ immune cells, the percentages of ILCs were higher in SqCCs than ADCs. Furthermore, the numbers of CD3 À RORgt þ ILC3, IL17 expression level, and IL23-or IL17RA-expressing tumor cells were associated with short survival of patients with SqCC but not ADC. Conclusions: Conversion from ILC1 into ILC3 by IL23producing SqCCs promotes IL17-mediated tumor progression, resulting in a poor prognosis.

Understanding the Complexity of the Tumor Microenvironment in K-ras Mutant Lung Cancer: Finding an Alternative Path to Prevention and Treatment

“…Clinically, numbers of ILC3s and levels of IL-17 are correlated with poor prognosis. Notably, these effects did not occur in adenocarcinoma, suggesting that the roles of these cells are quite heterogeneous among cancer types (225). ILC2s have been recently reported to secret amphiregulin, an EGFR ligand, which can promote lung tumor cell growth, facilitate resistance to apoptosis (226), and even interfere with antitumor immunity through stimulating Tregs and establishing an immunosuppressive TME (227).…”

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

“…reflected by the finding that high ILC3 numbers and IL-23 and IL-17 levels turned out to significantly correlate with decreased patient survival (204). An even higher level of flexibility in the ILC1/ILC3 ratio is achieved by the availability of local immature human ILCs (c-Kit + NKp44 − ), which can undergo differentiation toward either functional ILC1s or NKp44 + ILC3s in the presence of IL-2 and IL-12 or IL-2, IL-23, and IL-1β, respectively (15).…”

Progression or suppression: Two sides of the innate lymphoid cells in cancer

“…For instance, IL‐12 and IL‐1β promote ILC2 conversion into IFN‐γ‐producing ILC1. Furthermore, tumorgenesis may appear because of ILC1 conversion into NCR + ILC3 . In the tumor microenvironment, ILC activation can be triggered via damage‐associated molecular pattern (DAMP) signals related to the development of tumor and accessory cells .…”

“…Furthermore, tumorgenesis may appear because of ILC1 conversion into NCR + ILC3. 68 In the tumor microenvironment, ILC activation can be triggered via damage-associated molecular pattern (DAMP) signals related to the development of tumor and accessory cells. 16 Based on the soluble factors existing in the tumor microenvironment, each ILC subset might play an altered role in the progression of the tumor, and because of this, the ILC activation is dependent on a particular tissue environment.…”

“…5 A classic hallmark of ILCs is their ability in convert into each other as a consequence of pathogens, cytokines, tissue microenvironment signals 3 and the plasticity of ILCs has been reported in vitro and the microenvironment of many organs such as the intestine. 68 However, microenvironmental factors, contexts of tumor specificity and signaling intensity determine which side wins the conflict of being the pro-or anti-tumorigenic subset, 16 the tumor microenvironment reveals pro-inflammatory features that lead to tumor progression irrespective of whether tumorigenesis was promoted via local inflammation or not. 15 Nevertheless, in a common tumor microenvironment, the ILCs functions are still slightly enigmatic.…”