The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion

Abstract

Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P ¼ .03-.001) and when CTLs are neutralized (P ¼ .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, inhibition of MLL1 in combination with anti-PD-L1 or anti-PD-1 antibody immunotherapy effectively suppresses pancreatic tumor growth in a FasL-and CTL-dependent manner. Conclusions: The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

“…27 In line with previous reports only a minority (30%) of all analyzed tumor specimens were classified as PD-L1 positive. 7,[28][29][30] However, PD-L1 expression might differ between primary tumor and metastases as described for renal cell carcinoma and lung adenocarcinoma.…”

“…[31][32][33] Therefore, it must be pointed out that a majority (57%) of tumor samples in our study was from metastatic sites, while previous studies in PC determined PD-L1 expression in the pancreatic primary. 7,[27][28][29][30] In lymphoma patients, levels of sPD-L1 have been reported to be independent of tumoral PD-L1 expression. 15 Likewise, tumoral expression of PD-L1 did not correlate to serum levels of its soluble counterpart in our patient population.…”

Media studies to enhance the production of verticillins facilitated by in situ chemical analysis

“…Of these, verticillins are one of the most interesting for a variety of reasons [20, 48, 49, 58, 79]. This class of bioactive fungal secondary metabolites (as exemplified by compounds 1–7 ) is characterized by a dimeric structure [24] and is a key member of the epipolythiodioxopiperazine (ETP) alkaloids.…”

Epigenetics in Melanoma Development and Drug Resistance

“…For example, H3K4me3 dependent PD-L1 expression has been observed in pancreatic cancer [102] or H3K27me3 and DNA methylation-mediated silencing of Th1-type chemokines CXCL9 and CXCL10 in ovarian cancer cells [103], suggesting an important role for histone modifications in the regulation of immunomodulatory factors across different cancer types. Further evidence of epigenetically regulated PD-L1 expression is provided by studies using HDAC inhibitors in melanoma cell lines.…”