Lung Cancers Regulate The Immune Suppressor Pd-L1 By Multiple Mechanisms, Altering Its Role In Tumor Survival

The immune system has multiple mechanisms by which it can eliminate cancer and yet, tumors are able to adapt resistance to host immune surveillance and continue to survive and grow. One critical resistance mechanism involves Programmed cell death 1 ligand 1 (PD-L1, CD274, B7-H1), the predominant ligand for PD-1, an inhibitory receptor expressed on T cells following activation. PD-L1 also binds to B7.1 (CD80), inhibiting its ability to provide an immune stimulatory signal. PD-L1 is expressed broadly on multiple peripheral blood mononuclear cell subtypes, placenta, and numerous cancers, including NSCLC. Tumor-specific T cells infiltrate tumors and recognize tumor cells, releasing Interferon-gamma (IFNγ), initiating signaling of the Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway in the tumor cells. IFNγ induces and/or greatly enhances the expression of PD-L1 in the tumor, among other cell types, allowing the tumor to become resistant to the host T cell response. Blockade of PD-L1 binding to PD-1 and B7.1 can reinvigorate the host immune response against the tumor and overcome tumor adaptive resistance. The regulation of PD-L1 expression is complex and likely involves multiple types of pre- and post-translational events. We show that basal PD-L1 expression levels can vary greatly in cancer cells, as can PD-L1 induction by IFNγ. Here we describe the different categories of PD-L1 basal expression and IFNγ–dependent regulation across multiple lung cell lines and human tumor samples. Reverse Phase Protein Array and RNA microarray data show that the JAK/STAT canonical pathways are still intact among all of these distinct categories, so alternative mechanisms of expression regulation must be active in these cell lines and tumor samples. We provide evidence that a combination of mechanisms regulate both the basal and stimulated expression levels of PD-L1 across these distinct categories. This data regarding PD-L1 expression regulation provides valuable information to better understand the PD-1/PD-L1 pathway as a therapeutic target. Citation Format: Edward (Ward) E. Kadel, Kimberly Walter, Rupal Desai, Juliet Carbon, Marigold Boe, David Shames, Marcin Kowanetz. Lung cancers regulate the immune suppressor PD-L1 by multiple mechanisms, altering its role in tumor survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4978. doi:10.1158/1538-7445.AM2013-4978