No abstract

Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.

The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBV-related hepatocarcinogenesis. GRP78, GRP94, and HSP90 may be important prognostic markers of HBV-related HCC, strongly suggesting vascular invasion and intrahepatic metastasis.

The impact of pretreatment nutritional status on the treatment outcome of non-Hodgkin lymphoma has never been explored. Among the 953 patients who were registered in a prospective cohort at Samsung Medical Center., we analyzed 262 patients who had been treated with Ruximab-cyclophosphamide, doxorubicin, vincristine, and prednisone for newly diagnosed diffuse large B-cell lymphoma (DLBCL) and for whom data were available regarding pretreatment nutritional status. Nutritional status at diagnosis was assessed by triceps skin fold (TSF), mid-arm muscle circumference (MAMC), body mass index (BMI), serum albumin, prealbumin, and transferrin. For patients aged 60 yr and older, poor performance and higher tumor burden were associated with malnourishment represented by albumin <3.5 g/dL, prealbumin < 17 g/dL, and transferrin <170 mg/L. Lower BMI (<20), serum albumin, prealbumin, and transferrin were identified as risk factors for febrile neutropenia in univariate analysis, but not in multivariate analysis. In the univariate analysis for OS, all nutritional parameters except MAMC showed a significant association with survival. However, BMI was the only parameter that was independently prognostic for OS in the multivariate analysis (P = 0.031; hazards ratio = 3.32). Nutritional insufficiency encountered in DLBCL patients might influence the occurrence of treatment-related toxicity and poor survival outcome of patients.