IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

Abstract

Background:PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear.Methods:The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed.Results:The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01).Conclusions:Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

“…S4a) that would be expected to negatively impact antitumor CD8 C T cell activity in vivo. 29,30 Consistent with the known capacity of IFNg to upregulate PD-L1 expression in some tumors, 31 we observed that culturing RENCA cells in media supplemented with rmIFNg resulted in increased PD-L1 expression (Fig. S4b).…”

“…However, chronic inflammation in the TME (mediated by T cells or NK cells) may lead to upregulated expression of immune checkpoint molecules such PD-L1. 31,53,54 in the tumor, which can subvert or delete protective PD-1 C T effector cells. Consistent with this paradigm, we observed that effective vaccination against DLK1/DLK2 led to increased numbers of inflammatory (IFNg C ) TIL and to upregulated PD-L1 expression in the TME.…”

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…49 Furthermore, IFNγ has been shown to induce PD-L1 on the majority of tumor cell lines tested across many tumor types including panel of ovarian and pediatric tumors. 6,49,50 In this study NK cells induced PD-L1 on most cell line tested including leukemia, lung, colon and ovarian cancer cell lines. Recently, oncolytic vaccinia virus (OV) has been shown to also lead to induction of PD-L1 largely through IFNγ produced by immune cells recruited into tumor milieu in response to viral infection and its efficacy was improved by PD-L1 blockade.…”

“…4 Previous studies have established that expression of PD-L1 on most tumors is initially induced in response to IFNγ secreted by CD8 T cells recruited to the tumor site as part of adaptive tumor resistance. 5,6 Thus, treatment with adoptive transfer of IFNγ producing cell populations, such as activated NK cells, should lead to an increase in PD-L1 expression on tumor targets. NK cells not only produce IFNγ and other cytokines, which are secreted upon recognition of the tumor, but also recruit and orchestrate responses by other immune cells such as T- and dendritic cells in the tumor bed.…”

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

“…Tumour cells can interact with immune cells in the tumour microenvironment through the expression of immune-associated molecules, such as programmed cell death ligand 1 (PD-L1), IDO1, high-mobility group box-1 protein (HMGB1), CCL5 and CXCL2. Among these molecules, PD-L1 and IDO1 can directly suppress T cells [41,42], HMGB1 and CCL5 can enhance T reg -mediated immunosuppression [43,44] and CXCL2 can lead to immune tolerance by attracting myeloid-derived suppressor cells (MDSCs) to the tumour microenvironment [45].…”