IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer

Abstract

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which and ( ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. mice globally lacking in ( ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103 dendritic cells, and adoptive transfer of -sufficient CD4 T cells reversed early tumor development and metastasis in mice. Together, these findings support a key role for Th17 cells in TILs associated with the model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. .

Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses

“…In the Pts4 d/d model, there is an increase in Th17 cell infiltration, both before and after tumor development; however, after tumor development, there is an additional increase in the relative abundance of exhausted PD-1 + T cells and cytotoxic T lymphocytes (CTLs) in addition to increased Th17 cells. Furthermore, a decrease in Th17 cells and an increase in PD-1 + T cells have been found in the mediastinal lymph nodes in both NSCLC patients and Pts4 d/d mice (11). The expression of pro-inflammatory molecules in the Pts4 d/d model has not been reported.…”

“…Th17 cells can be generated under activation of oncogene or inhibition of tumor suppressors in both human and murine models (9-11). Oncogenic-driven NSCLC models have predominantly shown a pro-tumorigenic role of IL17A responses (9, 10), whereas IL17A regulation in a loss of tumor suppressor NSCLC model has been associated with an anti-tumorigenic function (11).…”

“…Furthermore, the same immune milieu (e.g., TILs abundant in Th17 cells), may have opposing effects on tumor establishment and or progression. An example of this dichotomous response to IL17A has been shown in K-ras vs. non-K-ras models of NSCLC, where IL17A was shown to promote growth in K-ras-driven tumors (10), but IL17A were required to inhibit early oncogenesis in a non-K-ras driven model (11). Specifically, mice with airway specific deletion of Phosphatase and tensin homolog (Pten) and SMAD family member 4 (Pts4 d/d ) spontaneously develop NSCLC by 9 months of age (55); global deficiency of Il17a resulted in earlier and increased metastasis which could be rescued with adoptive transfer of IL17a-sufficient CD4 + T cells (11).…”

“…In contrast to cancer-promoting effects of IL17A described above, IL17A has been shown to repress tumor development. In a non-K-ras model of NSCLC model Pts4 d/d (55), Th17 cell infiltrated the lungs before-and in early-stages of NSCLC (11). Immune competent Pts4 d/d mice lacking I117a showed accelerated tumor progression and metastasis, indicating that IL17A plays a beneficial role in anti-tumor responses (11).…”

“…Recently, growing evidence indicates that tumorintrinsic genetics determine the corresponding immune profile. To further understand how tumor mutations impact Th17/IL17A response, we review the role of this response in human tumors as well as the studies in K-ras vs. non-K-ras driven NSCLC (9)(10)(11). We also discuss immunotherapies and offer possible molecular and metabolic mechanisms that modulate Th17 cells in tumors.…”