Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8 + T cell exhaustion
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Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors.
Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1.
Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.
The mechanism underlying the potential risk associated with in vitro fertilization and embryo transfer (IVF‑ET) has been previously investigated but remains to be fully elucidated. As the placenta is a critical organ that sustains and protects the fetus, this is an important area of research.
The aim of the present study was to determine the difference in trophoblast cell function in the first trimester between naturally conceived pregnancies and pregnancies achieved via IVF‑ET therapy. A total of 20 placental villi in first trimester samples were obtained through fetal bud aspiration from patients undergoing IVF‑ET due to oviductal factors between January 2016 and August 2018.
In addition, a further 20 placental villi were obtained from those who naturally conceived and had normal pregnancies but were undergoing artificial abortion; these patients were recruited as the controls. Reverse transcription‑quantitative (RT‑q)PCR and semi‑quantitative immunohistochemical methods were used to detect the mRNA and protein expression of α‑fetoprotein (AFP), vascular endothelial growth factor (VEGF), transferrin (TF), tubulin β1 class VI (TUBB1), metallothionein 1G (MT1G), BCL2, glial cells missing transcription factor 1 (GCM1), epidermal growth factor (EGF) receptor (EGFR), PTEN and leukocyte associated immunoglobulin like receptor 2 (LAIR2) in villi from both groups.
Differentially expressed genes were analyzed using Search Tool for the Retrieval of Interacting Genes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted. The RT‑qPCR data revealed that the mRNA expression levels of AFP, VEGF and TF were significantly higher in the IVF‑ET group than in the control group (P<0.05), and those of TUBB1, MT1G, BCL2, GCM1, EGFR, PTEN and LAIR2 were significantly lower (P<0.05).
These gene products were expressed in the placental villus tissues, either in the cytoplasm, or in the membrane of syncytiotrophoblast and cytotrophoblast cells. The immunohistochemistry results were in line with those observed using RT‑qPCR. KEGG pathway analysis indicated that the trophoblast cell function of the IVF‑ET group in the first trimester was different from naturally conceived pregnancies with regard to proliferation, invasion, apoptosis and vascular development. The IVF‑ET process may trigger adaptive placental responses, and these compensatory mechanisms could be a risk for certain diseases later in life.
The placenta is a temporary vital organ for intra-uterine development and growth. The anatomical structure of the placenta has evolved substantially, resulting in broad inter-species diversity. In particular, human placental extravillous trophoblast cells (EVTs) have evolved aggressive features, although the mechanism underlying this aggressiveness remains elusive. In the present study, we compared the human and mouse homologous gene databases and obtained 2272 human-specific genes, 807 of which are expressed in the placenta according to the UniGene database.
Using the human trophoblast cell line HTR8/SVneo, we further verified the expression and function of one of these genes, the leukocyte-associated immunoglobulin-like receptor 2 (LAIR2). This gene shows increased expression during pregnancy and its reduced expression is associated with pregnancy complications. Although LAIR2 was expressed in the human placenta villus and decidua in the first trimester of pregnancy, it was not expressed in mouse tissues.
Knockdown of LAIR2 markedly improved cell viability and inhibited the invasive ability of HTR8/SVneo cells. These data suggest that species-specific genes are pivotal to the evolution of a more aggressive human placenta to match the physiological demands of human development. Further investigation is required to obtain evidence on the function of LAIR2 and other specific genes in the placenta, providing insight on the mechanism, properties, and possible applications of this in humans.
Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.
Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL.
We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma.Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL.
In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p < 0·01) compared to controls.This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL.NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.