Chemotherapy agents-induced immunoresistance in lung cancer cells could be reversed by trop-2 inhibition in vitro and in vivo by interaction with MAPK signaling pathway

Abstract

Chemotherapy has been widely used in cancer treatment, but the prognosis of the cancer patients following chemotherapy has not been substantially improved. Alternative strategies such as immunotherapy and their combinations with chemotherapy are now being considered; however, the effects of chemotherapy on the immune responses of cancer cells are not fully understood. In the present studies, we reveal a potential link between chemotherapy and cancer immunoresistance, we first examined the effects of chemopreventive agent DDP on the expression of a cell surface glycopreotein Trop-2 in lung cancer cells, and found that DDP not only induce Trop-2 surface expression in human lung cancer cells, but also induce T-cell apoptosis effectively. In order to investigate the relationship between DDP-induced Trop-2 expression and T-cell apoptosis, we stably transfected A549 and PC14 lung cancer cells with Trop-2 shRNA, the DDP-induced Trop-2 surface expression was effectively decreased in stably transfected cell lines, but chemotherapeutic reagent-induced cell proliferation inhibition and apoptosis were increased through inhibition of the MAPK signaling pathway. In vivo animal experiments showed that Trop-2 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, DDP treatment exhibited a strong antitumor activity in the mice with Trop-2 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that DDP resistance in lung cancer cells could be induced through increased surface expression of Trop-2, which at least partially by interfering with MAPK pathway. These results provide novel insight into the function of Trop-2 and encourage the design and testing of approaches targeting this protein and its partners.

<p>Targeting Trop-2 in solid tumors: future prospects</p>

“…Additionally, Trop-2 is a strong predictor of cancer response to AKT inhibitors, and as such AKT inhibitors seem to be a rational target for further investigation along with Trop-2-targeted therapy 70. Moreover, Wang et al have demonstrated that increased Trop-2 expression is associated with cisplatin resistance in lung cancer cells 71. Given the benefit of IMMU-132 (sacituzumab govitecan) therapy, which provides additional benefit at lower dosages than using irinotecan, this study demonstrates additional potential benefits of combining Trop-2-targeted therapeutics and traditional DNA-damaging chemotherapy, as we theorize Trop-2 inhibition may sensitize cells to DNA-damaging chemotherapy.…”

Trop2: Jack of All Trades, Master of None

“…In prostate cancer xenografts, Trop2 was upregulated in relapsed tumors after flutamide and docetaxel treatment and Trop2 enhanced recovery of androgen-sensitive, but not androgen-resistant cells, after exposure to docetaxel [ 145 ]. Silencing Trop2 using shRNA resulted in increased sensitivity to cisplatin in lung and cisplatin/5-fluorouracil in gastric cancer cells in vitro and in vivo [ 146 , 147 ].…”

Immune reconstitution from peripheral blood mononuclear cells inhibits lung carcinoma growth in NOD/SCID mice

“…The drug-surviving cells (DSCs) are responsible for tumor regeneration after chemotherapy, and may be one of the mechanisms involved in drug resistance ( 3 ). Immunoresistance induced by chemotherapy agents may be another mechanism ( 4 ). Am1010, a new DSC line, was established in our previous study from an arm muscle metastasic tumor of a patient diagnosed with lung adenocarcinoma ( 5 ).…”