Thus, this study showed that changes in sGAL-9 levels were associated with smoking and shorter overall survival in NSCLC. Galectins contribute to carcinogenesis and cancer progression, including cancer, proliferation, metastasis, angiogenesis, and the immune response .
This study also showed high sGAL9 and better OS in non-smokers NSCLC patients than smokers. Tobacco smoke contains many chemical and carcinogenic particles that could develop chronic pulmonary inflammation and lung cancer. Curiously, the lung cancer of smokers and non-smokers have distinct inflammatory signatures, with marked differences in mast cell and CD4+ T cell numbers. Furthermore, high regulatory T cells, even at early stages, and reduced CD8+ T cells in the tumor lesion; have been related as an immune escape mechanism in NSCLC patients .
High sGAL9 levels were associated with a better prognosis in OS analysis compared to the patients' group with low sGAL9 levels. Thus, we can infer that smoking not only could damage immune system processes due to chronic pulmonary inflammation, with reduction of sGAL9 levels but also favors the onset of LC and its worse prognosis. A limited number of studies have investigated the role of GAL9 in lung cancer. Increased GAL9 expression in tumor cells may suppress pulmonary metastasis, recurrence of melanoma, and breast cancer .
Kadowaki et al. 2013 shown in lung carcinoma cell-bearing mice that GAL9 expression induces macrophage differentiation into plasmacytoid dendritic cell-like macrophages, which may augment the activation of NK cells and was associated with, increased the survival of tumor-bearing mice . Only 15%–20% of NSCLC patients under immune checkpoint inhibitor treatment achieve a partial or complete response. The resistance mechanism to immunotherapy needs to be better-understood . One study showed that early accumulation of monocytic myeloid-derived suppressor cells expressing GAL9 .
The analysis of expression of GAL-9 is on NSCLC tumor cells, and tumor-infiltrating lymphocytes (TILs) showed that low GAL9 levels on tumor cells or high GAL-9 levels on TILs were more likely to have a poor prognosis. GAL-9 on TILs correlated with TIM-3, PD-1, and PD-L1 levels, and on tumor cells, GAL-9 was associated with the expression of TIM-3 . D'Alessandro et al. 2020 demonstrated that Galectins 1, 3, and 9 levels have been changed in serum idiopathic pulmonary fibrosis, suggesting their potential utility as clinical, diagnostic, and prognostic biomarkers .
In NSCLC patients, high TIM-3 and GAL-9 levels correlated with larger tumor sizes, advanced stages, and more distant metastasis . Lymphoid cells with high TIM-3 expression are associated with primary and secondary resistance in metastatic LC patients under anti-PD-1 treatment . Moreover, TIM-3 is often co-expression with PD1 in exhausted CD8 cells in infections and tumors, which could explain why an isolated blockade of TIM-3 could be effective .
This study indicated the predictive accuracy of sGAL9 in the survival advanced NSCLC. We suggest that changes in sGAL9 levels could be associated with smoking and deaths in lung cancer. However, an increase of GAL9 levels in the serum of non-smokers patients was associated with a better OS in advanced NSCLC. In conclusion, sGAL9 is a potential biomarker predictive of OS in advanced NSCLC.