Prevalence of PD-L1 in Cervical Cancer Patients and the Potential for Combining an Immune Checkpoint Inhibitor With Lenvatinib

Background/Aim: Cervical cancer is the fourth
most common cause of cancer-related deaths in women
worldwide. The potential for targeted therapy against the
immune checkpoint programmed death 1 (PD-1)/programmed
death-ligand 1 (PD-L1) and receptor tyrosine kinases was
examined in cervical cancer patients and cell lines. Materials and Methods: On tissue microarrays, PD-L1 was analyzed in
123 samples of patients with cervical cancer using
immunohistochemistry. In SiHa, HeLa, and CaSki cervical
cancer cell lines we examined the combination of lenvatinib
with a PD-1/PD-L1 inhibitor using cell viability assays, the
activation of cell signaling pathway proteins using western
blots and gene expression using quantitative reverse
transcriptase-PCR. Results: Of 113 evaluable samples, 90
(79.6%) had more than 1% PD-L1 positive cells. The single
treatment with the PD-1/PD-L1 inhibitor resulted in the
greatest reduction in growth for CaSki and lenvatinib in HeLa
cells. In contrast, the combined treatment of lenvatinib with
the PD-1/PD-L1 inhibitor demonstrated a significantly
stronger impeded proliferation compared to the single
treatment in all three cell lines. Moreover, the combined
treatment caused significantly less phosphorylation of the
signaling molecules ERK and S6 in SiHa and of S6 and
STAT3 in HeLa cells but not in CaSki. All treatments
diminished the mRNA levels of PD-L1, Il-8, and FGFR in
SiHa cells. Conclusion: PD1 is frequently expressed in
cervical cancer samples. Combining lenvatinib with a PD-
1/PD-L1 inhibitor diminished proliferation of cervical cancer
cell lines. Consequently, this combination might be a
promising option to treat cervical cancer. Signaling pathways
involved in tumor cell growth are blocked by the combined
treatment but still a model of the underlying mechanism
cannot be drawn.