In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.
Copyright © 2024. Published by Elsevier Inc.

The efficacy of chemotherapy varies significantly among patients with gastric cancer (GC), and there is currently no effective strategy to predict chemotherapeutic outcomes. In this study, we successfully establish 57 GC patient-derived organoids (PDOs) from 73 patients with GC (78%). These organoids retain histological characteristics of their corresponding primary GC tissues. GC PDOs show varied responses to different chemotherapeutics. Through RNA sequencing, the upregulation of tumor suppression genes/pathways is identified in 5-fluorouracil (FU)- or oxaliplatin-sensitive organoids, whereas genes/pathways associated with proliferation and invasion are enriched in chemotherapy-resistant organoids. Gene expression biomarker panels, which could distinguish sensitive and resistant patients to 5-FU and oxaliplatin (area under the dose-response curve [AUC] >0.8), are identified. Moreover, the drug-response results in PDOs are validated in patient-derived organoids-based xenograft (PDOX) mice and are consistent with the actual clinical response in 91.7% (11/12) of patients with GC. Assessing chemosensitivity in PDOs can be utilized as a valuable tool for screening chemotherapeutic drugs in patients with GC.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

It is well known that chimeric antigen receptor T-cell immunotherapy (CAR-T-cell immunotherapy) has excellent therapeutic effect in haematological tumours, but it still faces great challenges in solid tumours, including inefficient T-cell tumour infiltration and poor functional persistence. Flap structure-specific endonuclease 1 (FEN1), highly expressed in a variety of cancer cells, plays an important role in both DNA replication and repair. Previous studies have reported that FEN1 inhibition is an effective strategy for cancer treatment. Therefore, we hypothesized whether FEN1 inhibitors combined with CAR-T-cell immunotherapy would have a stronger killing effect on solid tumours. The results showed that low dose of FEN1 inhibitors SC13 could induce an increase of double-stranded broken DNA (dsDNA) in the cytoplasm. Cytosolic dsDNA can activate the cyclic GMP-AMP synthase-stimulator of interferon gene signalling pathway and increase the secretion of chemokines. In vivo, under the action of FEN1 inhibitor SC13, more chemokines were produced at solid tumour sites, which promoted the infiltration of CAR-T cells and improved anti-tumour immunity. These findings suggest that FEN1 inhibitors could enable CAR-T cells to overcome poor T-cell infiltration and improve the treatment of solid tumours.
© 2023 John Wiley & Sons Ltd.

Background Among people with HIV (PWH), lung cancer is the leader cause of cancer mortality, with increased risk and poor clinical outcomes compared to people without HIV (PWOH). HIV is known to result in persistent global immune dysfunction despite antiretroviral therapy, but little is known about the lung cancer tumor microenvironment. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) is associated with an immunoregulator environment that limits tumor-specific immune responses. Methods A tissue microarray was constructed with NSCLC tumors from 18 PWH and 19 PWOH (matched for histological subtype, stage, year of diagnosis, age, sex and smoking status), and incubated with metal-conjugated antibodies for evaluation by imaging mass cytometry (IMC). IMC marker scores were extracted by automated cell segmentation and single-cell data was analyzed by Phenograph using unsupervised cell-segmentation and clustering of cells. Evaluation of tumor infiltrating immune cells, CD4+ and CD8+ T cells as well as CD68+ tumor associated macrophages were characterized for marker expression using a linear mixed-effects model. Additionally, a computational strategy based on the PageRank mathematical algorithm was used in order to establish an unsupervised and cell segmentation-independent signature associated with HIV status to discriminate differential expression of immune cell markers within the TME of the two groups. Peripheral blood mononuclear cells (PBMCs) from HLA-A02 donors (PWH and PWOH) were co-incubated with HLA-A02 lung cancer cell lines to quantify tumor killing (by Annexin V staining) and expression of T cell markers Lag-3 and CD25. Results Within the TME from HIV+ tumors, there is comparable level of infiltration of lymphocytes and tumor associated macrophages (TAMs) compared to non-HIV tumors, with a trend towards increased CD8+ T cells and decreased CD4:CD8 ratio among HIV+ tumors. Using a random effects model of individual markers, HIV+ tumors revealed increased expression of Ki67 and Granzyme B (GRZB) among CD8+ T cells; increased Ki67 and PD-1 among CD4+ T cells; and increased PD-L1, PD-L2, and Ki67 among TAMS. Unsupervised clustering analysis from IMC data demonstrated differential distribution of tumor infiltrating CD8+ T cell clusters between HIV+ and non-HIV tumors, defined by marker expression patterns. Three clusters were significantly elevated in HIV+ tumors (57.1% vs. 21.7% in non-HIV tumors, p<0.0001). All three clusters had comparatively elevated PD-1 and Lag-3 expression with varying expression of activation and proliferation markers CD25 and Ki67. Within tumor-infiltrating CD4+ T cells, a cluster characterized by checkpoint protein expression (PD-1+ and LAG-3) was also highly represented in HIV+ cases (35.2% vs. 9.8% in non-HIV cases, p<0.0001). HIV+ tumor-associated macrophages (TAM) had higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1 and VISTA), confirmed by the expansion of three clusters comprising 58.8% of TAMs vs. 17.8% in non-HIV tumors (p<0.0001). Discrimination of cells between HIV+ and HIV-TME was further confirmed by spectral graph theory with 84.6% accuracy, with a combination of markers on TAMs and T cells. Lastly, PBMCs from PWH exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines compared to PBMCs from PWOH. CD8+ T cells from PWH additionally had increased expression of immune checkpoint inhibitor Lag-3 upon exposure to tumor cells. Conclusions Our study demonstrates that the TME of HIV+ patients is characterized by a unique immune landscape, distinct from that of PWOH, with evidence of expansion of immune cells with enhanced immunoregulatory phenotypes and associated with impaired anti-tumor responses.

Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy.
Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer.
Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8+ T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8+ T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-β levels through GPR30-AKT signaling, thereby enhancing CD8+ T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8+ T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models.
A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8+ T cell function through the upregulation of PD-L1, IL-6 and TGF-β via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.
© 2023. The Author(s).