EGFR-TKIs play a dedicated therapeutic effect on NSCLC carrying EGFR sensitive mutations, such as EGFR 19 exon in-frame deletion(19DEL) and substitutional mutation of arginine for leucine (L858R) in exon 212, 4, 19. Although EGFR-TKIs exhibited spectacular therapeutic benefits in clinical practice, the occurrence of adverse effects can not be ignored at any time. Adverse events may impact the efficacy of anticancer therapies even result in treatment termination and disease progression. In addition to the reduction or stabilization of local lesions, systemic or local inflammatory reactions also occur in patients during the whole process of EGFR-TKIs therapy18. Common inflammatory reactions including rash, paronychia and chondriasis, hair disorders, mucitis, etc. Other inflammatory reactions include interstitial pneumonitis, chronic inflammation of intestinal tract and liver20–22.
As an immune modulator, LP is generally prescribed in the treatment of numerous malignant tumors. Previous studies pointed out that LP can regulate the body’s immune function so as to improve physical condition of cancer patients and diminish cancer/treatment-related painfulness or adverse effects15. Additionally, LP administration could elevate the cellular level of CD3+, CD4+ and NK cells in malignant cancer patients who underwent radiotherapies, which proved that LP could enhance the body's cellular immunity and reduce the toxicities of radiotherapy16. Similarly, our study showed higher levels of CD3+, CD4+ and the ratio of CD4+/CD8+ in advanced NSCLC patients treated by LP combined with Gefitinib. CD3+ T cell is representative of whole immune cells level, normally the ratio of CD4+/CD8+ is larger than 1, the bigger the ratio is, the greater number of helper T cells are, and corresponding the less suppressor T cells are, which reflects a better immune status. Furthermore, increased CD4+/CD8+ ratio can serve as an independent prognostic factor in NSCLC23–26.
Our study innovatively found that LP showed a synergistic antitumor effect and could enhance the efficacy of EGFR-TKIs. LP combined with Gefitinib exhibited a more magnificent inhibitory capability on tumor cell biological behavior. More importantly, LP showed a synergistic effect in blocking G0/G1 phase transition to inhibit tumor cell proliferation in our study. A study focused on the combination therapy of cyclophosphamide (CTX) with LP based on murine lung carcinoma model pointed out that LP itself did not possess the property of direct antitumor effect, but it showed a synergistic enhancing phenomenon of antitumor effect when applied with CTX27. This probably attribute to LP relieving immunosuppressive tumor microenvironment by stimulating and activating lymphocytes in tumor microenvironment. Likewise, that might explain the tinny difference between the LP group and control group in our study.
Taken together, our study demonstrated that LP in conjunction with Gefitinib could enhance body immune function so that empower patients tolerate longer treatment exposure and derive more benefit from EGFR-TKIs therapy, accordingly, arriving longer survival time. Furthermore, LP promotes the sensitivity of PC9-GR cells to EGFR-TKIs, arrests cell cycle, inhibits tumor proliferation, invasion and migration, as well as plays an important role in reducing the expression of phosphorylation of EGFR protein, and consequencely enhances anticancer effect of EGFR-TKIs therapy. In conclusion, LP in combination with Gefitinib was an effective treatment for patients of advanced NSCLC, which may improve the life quality of patients, and potentially improve prognosis. Further investigations are still required to explore the specific mechanisms to enhance the immunity of LP.