Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer

Abstract

Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-kB-dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8 þ T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-kB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-kB-mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer. Cancer Res; 75(23);5034-45. Ó2015 AACR.

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…Conversely, some ICD inducers appear to increase the expression of checkpoint inhibitors and their ligands. The expression of these immunosuppressive molecules, including PD1 and PD-L1, is upregulated on tumor cells or immune cells following radiotherapy, ICD chemotherapy, and type I IFN induction (51,53,65,(71)(72)(73). We found that dinaciclib induced PD-L1 expression on tumor cells in vitro, even after a short exposure to the drug.…”

“…Despite ICD induction, the antitumor activity of dinaciclib as a monotherapy was limited, and only in combination with anti-PD1 Ab did dinaciclib enhance tumor suppression (Figure 1, A-C). Recent studies have shown that the induction of PD1 and PD-L1 expression on tumor and associated immune cells can suppress radiation-or chemotherapy-induced immune responses (50,51), and type I IFN signaling plays an important role in mediating PD1 expression on T cells in tumor (52)(53)(54). Similarly, we found increased expression of PD1 on tumor-infiltrating CD8 + T cells after in vivo dinaciclib treatment ( Figure 6A) and increased expression of PD-L1 on tumor cells after in vitro treatment (Supplemental Figure 8).…”

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

“…In cases with high IFNg activity and high PD-L1 expression, anti-PD-L1/PD-1 therapy alone is expected to be useful. We have shown that some chemotherapy reagents may induce PD-L1 expression in tumor cells (50). Therefore, during chemotherapy, using these drugs, the inclusion of anti-PD-L1/PD-1 therapy may augment the efficacy of the treatment.…”

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

“…Furthermore, recent mouse cancer experiments showed the efficacy of blocking the PD-1/PD-L1 axis following paclitaxel chemotherapy (17). The ability to sample HGSC biopsies at diagnosis and after NACT during surgery gives us an opportunity to ask whether similar responses occur in a clinical setting and if they do, whether this provides a rationale for introducing immunotherapy after NACT rather than in relapsed disease.…”