The IL-25/ILC2 axis promotes lung cancer with a concomitant accumulation of immune-suppressive cells in tumors in humans and mice

Abstract

BackgroundGroup 2 innate lymphoid cells (ILC2) can be activated by interleukin (IL)-33 or IL-25. IL-25-activated ILC2 cells help protect the host against helminth infection while exacerbating allergic-like inflammation and tissue damage in the lung. In the context of cancer, IL-33-activated ILC2 cells were found to bear anti-tumoral functions in lung cancer while IL-25-activated ILC2 cells promoted tumorigenesis in colorectal cancer. The role of IL-25-activated ILC2 cells in lung cancer remains to be addressed.MethodsWe examined the overall survival of human non-small cell lung cancer (NSCLC) patients according to IL25 expression as well as the distribution of ILC2 cells and regulatory T cells (Tregs) in various NSCLC patient tissues and peripheral blood (PB) of healthy donors (HDs). We analyzed the effect of adoptive transfer of IL-25-activated ILC2 cells on tumor growth, metastasis and survival in a heterotopic murine model of lung cancer.ResultsWe report that human NSCLC patients with high IL-25 expression have reduced overall survival. Moreover, NSCLC patients bear increased frequencies of ILC2s compared to HDs. Frequencies of Tregs were also increased in NSCLC patients, concomitantly with ILC2s. In mice bearing heterotopic lung cancer, adoptive transfer of IL-25-activated ILC2s led to increased tumor growth, increased metastasis and reduced survival. The frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs) were found to be increased in the tumors of mice that received ILC2s as compared to controls.ConclusionOverall, our results indicate that the IL-25/ILC2 axis promotes lung cancer potentially by recruiting immune-suppressive cells to the tumors both in humans and in mice, and that it may therefore represent a suitable novel target for NSCLC immunotherapeutic development.

Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy

“…Indeed, blocking other inhibitory receptors on ILC1s for example cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell Ig and ITIM domain (TIGIT) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) may similarly enhance ILC1 anti-tumour activity [ 63 , 64 ]. However, it is important to realise that ILC2s also express inhibitory checkpoint receptors such as PD-1, and therefore systematic administration of immune checkpoint inhibitors may simultaneously precipitate pro-tumoural functions of ILC2s particularly in cancer types such as CRC and lung cancer where ILC2s are found to promote tumorigenesis [ 4 , 5 , 65 , 66 ]. Indeed, the lack of efficacy of immune checkpoint inhibitors in the majority of CRC patients as seen in clinical trials may potentially be due to concomitant stimulation of pro-tumoural ILC2s offsetting the beneficial activation of anti-tumoural type 1 lymphocytes.…”