👤 Franca M di Summa

Immune checkpoint inhibitors (ICIs) have improved the metastatic melanoma (MM) treatment. However, a significant proportion of patients show resistance to immunotherapy, and predictive biomarkers for non-responders or high-risk recurring patients are currently lacking. Recent studies have shown that tumor-related metabolic fingerprints can be useful in predicting prognosis and response to therapy in various cancer types. Our study aimed to identify serum-derived metabolomic signatures that could predict clinical responses in MM patients treated with ICIs. A multivariable model was used to identify distinct prognostic factors for OS. Negative factors included glucose, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B-very low-density lipoprotein (ApoB-VLDL), whereas glutamine and free HDL cholesterol emerged as positive factors. They were then used to construct a risk score model able to stratify patients in prognostic groups. Similarly, a separate predictive risk score model for PFS was developed, focusing solely on glucose and apolipoprotein A1 (ApoA1) HDL. Threefold cross validation resulted in mean concordance indices of 0.72 and 0.74 for PFS and OS, respectively. Importantly, this analysis was replicated in patients who received first-line ICIs. Interestingly, the prognostic score for OS included glutamine, glucose, and LDL (low-density lipoprotein) triglycerides, whereas only glucose negatively influenced PFS. In this subset, the concordance indices increased to 0.81 and 0.9 for PFS and OS, respectively. Our data identified glycolipid signatures as robust predictors of distinct therapeutic outcomes in MM patients treated with ICIs. These results could pave the way for novel therapeutic approaches. Show less

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3 Show less

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window. To this end, we provide an original bioinformatic dissection of the gene expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient's derived samples indicated that WNT increased activation and a peculiar immune microenvironment identify subjects with nodal involvement. In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939-a specific WNT pathway inhibitor-has in re-educating a tumor-permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in node-positive disease. Show less

The regulation of translation initiation factor 2 (eIF2) is important for erythroid survival and differentiation. Lack of iron, a critical component of heme and hemoglobin, activates Heme Regulated Inhibitor (HRI). This results in phosphorylation of eIF2 and reduced eIF2 availability, which inhibits protein synthesis. Translation of specific transcripts such as Atf4, however, is enhanced. Upstream open reading frames (uORFs) are key to this regulation. The aim of this study is to investigate how tunicamycin treatment, that induces eIF2 phosphorylation, affects mRNA translation in erythroblasts. Ribosome profiling combined with RNA sequencing was used to determine translation initiation sites and ribosome density on individual transcripts. Treatment of erythroblasts with Tunicamycin (Tm) increased phosphorylation of eIF2 2-fold. At a false discovery rate of 1%, ribosome density was increased for 147 transcripts, among which transcriptional regulators such as Atf4, Tis7/Ifrd1, Pnrc2, Gtf2h, Mbd3, JunB and Kmt2e. Translation of 337 transcripts decreased more than average, among which Dym and Csde1. Ribosome profiling following Harringtonine treatment uncovered novel translation initiation sites and uORFs. Surprisingly, translated uORFs did not predict the sensitivity of transcripts to altered ribosome recruitment in presence or absence of Tm. The regulation of transcription and translation factors in reponse to eIF2 phosphorylation may explain the large overall response to iron deficiency in erythroblasts. Show less