Sijunzi Tang and gefitinib cooperate to inhibit Lung cancer progression by modulating the pre-metastatic niche

Abstract

Background:Although targeted therapies usually trigger great initial responses in patients, the efficacy is transient due to tumor metastasis. The formation of pre-metastatic niche was proposed as the main cause for metastasis, of which the blocking way may be a potential method for inhibiting metastasis. Sijunzi Tang (SJZ), as a complementary drug for targeted therapy, can reduce the recurrence and metastasis of tumors and prolong the survival time of patients. However, how SJZ regulates the formation of pre-metastatic niche to improve the efficacy of targeted therapy remains unclear.Methods: Here, we investigated the anti-tumor activity and immunological mechanism of SJZ plus gefitinib based on pre-metastatic niche in Lewis lung carcinoma (LLC) incubated spontaneous metastatic mouse model, using histopathology and immunological methods.Results:The results showed that SJZ can improve the effect of gefitinib by inhibiting tumor cell growth, promoting tumor cell apoptosis and preventing metastasis in the lung. Besides, SJZ plus gefitinib could inhibit tumor cell aggregation and the expression of characteristic proteins of Mmp2 and Mmp9 in the lung areas of mice. We also confirmed that SJZ could downregulate the expression levels of c-kit and VEGFR2 on DCs, c-kit on neutrophils, c-kit, VEGFR2 on B lymphocyte in the blood, and c-kit and CXCR1 on monocytes in the lung; Gefitinib could decrease the expression levels of c-kit and VEGFR2 on DCs in the blood and c-kit and CXCR1 on monocytes in the lung, but increase the amount of c-kit+ monocytes in the blood. SJZ plus gefitinib decrease the proportion of c-kit+ and CXCR1+ monocytes in the lung. SJZ could regulate pro-metastatic inflammatory responses represented by down-regulating the expression of IL-23，RANTES, GRO-α against that of gefitinib. Moreover, there were significant rises in the expression level of IL-12p70 and IL-15，while declines in the expression level of IL-1β、IL-18、GRO-α in co-treatment group.Conclusions: This work identified the immune cells and cytokines in pre-metastatic niche associated with lung cancer affected by gefitinib and SJZ, and further revealed the immunological mechanism of SJZ improving the efficacy of gefitinib.