NKG2D/CD28 chimeric receptor boosts cytotoxicity and durability of CAR-T cells for solid and hematological tumors.

Background: CAR-T cell therapy faces challenges in solid tumor treatment and hematologic malignancy relapse, among which the limited persistence of CAR-T cells and target antigen downregulation are prominent factors. Therefore, we engineered an NKG2D/CD28 chimeric co-stimulatory receptor (CCR), leveraging its broad ligand expression on tumors to enhance the antitumor activity of MSLN CAR and CD19 CAR-T cells.

Methods: We generated MSLN CAR-T and CD19 CAR-T cells co-expressing the NKG2D/CD28 CCR and assessed their antitumor efficacy in vitro and in vivo.

Targeted LNPs deliver IL-15 superagonists mRNA for precision cancer therapy.

Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate, but the therapeutic utility remains concern due to the unexpected systematic stress. Here, we propose that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. In the established Structure-driven TARgeting (STAR) platform, the LNP and LNP can effectively and selectively deliver optimized IL-15 superagonists mRNAs to local and lungs, respectively, in relevant tumor models.

Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy.

Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains.

Single-cell sequencing of tumour infiltrating T cells efficiently identifies tumour-specific T cell receptors based on the T cell activation score.

Adoptively transferred T cell receptor-engineered T cells are a promising cancer treatment strategy, and the identification of tumour-specific TCRs is essential. Previous studies reported that tumour-reactive T cells and TCRs could be isolated based on the expression of activation markers. However, since T cells with different cell states could not respond uniformly to activation but show a heterogeneous expression profile of activation and effector molecules, isolation of tumour-reactive T cells based on single activation or effector molecules could result in the absence of tumour-reactive T cells; thus, combinations of multiple activation and effector molecules could improve the efficiency of isolating tumour-specific TCRs.

Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration.

Background: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion.

Methods: AOM/DSS model in Il11 and Apc/Il11 mice were used to detect tumor growth and CD8 T infiltration.

Autophagic flux restoration enhances the antitumor efficacy of tumor infiltrating lymphocytes.

Background: Although adoptive cell therapy with tumor infiltrating lymphocytes (TILs) has mediated effective antitumor responses in several cancers, dysfunction and exhaustion of TILs significantly impair the therapeutic effect of TILs. Thus, it is essential to elucidate the exhausted characteristics of TILs and improve the antitumor effect of TILs by reversing their exhaustion. Here, we focused on the influence of autophagy on TILs in terms of T-cell activation, proliferation, and differentiation in vitro and in vivo.

Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells.

Objectives: Although adoptive cell therapy with T-cell receptor-engineered T cells (TCR-Ts) has mediated effective antitumor responses in several cancers, senescence of T cells could impair the therapeutic effect of TCR-Ts. Thus, it is essential to elucidate the characteristics of senescent TCR-Ts and how to subsequently improve their antitumor effect. Here, we focused on the influence of autophagy on TCR-Ts, since autophagy is tightly associated with the regulation of T-cell activation, proliferation and differentiation.

Blockade of IL-6 inhibits tumor immune evasion and improves anti-PD-1 immunotherapy.

Long-standing inflammatory bowel disease predisposes to the development of colorectal cancer (CRC). Interleukin (IL) -6, a pivotal link between chronic inflammation and tumor progression, has recently been recognized as a potential therapeutic target. The effect of IL-6 on proliferation and metastasis of CRC by activating the STAT3 pathway has been widely demonstrated in recent years, but few on mediating tumor immune evasion.

Clonal Distribution and Intratumor Heterogeneity of the TCR Repertoire in Papillary Thyroid Cancer With or Without Coexistent Hashimoto's Thyroiditis.

The intratumor heterogeneity (ITH) of the amount and TCR repertoires of tumor infiltrating lymphocytes (TILs) in PTC with and without coexistent Hashimoto's thyroiditis (HT) are unclear. Here, we investigated the amount of T cells in tumor and corresponding normal tissues by immunohistochemical staining on 80 tumor samples and 40 normal samples from 40 patients. The immune repertoire of T cells was identified on 24 tumor samples and 12 normal samples from 12 patients using TCR high-throughput sequencing.

Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity.

The inadequate in vivo persistence of chimeric antigen receptor (CAR)-modified T cells has been shown to lead to poor therapeutic efficacy and disease recurrence. In vivo persistence is associated with the differentiation subsets infused, with less differentiated T or T conferring superior renewal capacity and antitumor immunity compared to T or T. However, ex vivo expanded CAR-T cells exhibit phenotypic heterogeneity with majority of T or T subsets and very low populations of T and T.

Induction of EBV latent membrane protein-2A (LMP2A)-specific T cells and construction of individualized TCR-engineered T cells for EBV-associated malignancies.

Background: Latent membrane protein-2A (LMP2A)-specific TCR-engineered T cells could be a promising treatment approach to Epstein-Barr virus-associated malignancies. However, previous studies mainly reported LMP2A-reactive TCRs only focusing on specific HLA subtypes and corresponding epitopes, and thus, they were only suitable for patients with specific HLA.

Methods: Due to hugely varied HLA subtypes and presented LMP2A epitopes in different individuals, our study attempted to develop an individualized approach, based on the weekly in vitro stimulation of peripheral T cells for 2 weeks with autologous dendritic cells (DCs) pulsed with a pool of LMP2A peptides covering LMP2A whole protein and combination analysis of high throughput TCRβ sequencing of prestimulated and poststimulated T cells and single-cell TCR sequencing of poststimulated T cells, and to identify LMP2A-specific TCRs of which poststimulated frequencies significantly increased than corresponding prestimulated frequencies.

CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies.

CD19-targeted chimeric antigen receptor T (CAR T) cell therapy is a promising option to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, the majority of CAR T-treated patients will eventually progress and require salvage treatment, for which there is no current standard. In this study, we analyzed data from 6 patients with R/R DLBCL who experienced progression following CD19-CAR T therapy, and then received CD19-specific CAR T cells that express a PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR T) as salvage therapy at our institution.

Oral microbiome and risk of malignant esophageal lesions in a high-risk area of China: A nested case-control study.

Objective: We aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk.

Methods: We conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls.

Pre-depletion of TRBC1+ T cells promotes the therapeutic efficacy of anti-TRBC1 CAR-T for T-cell malignancies.

Targeting T cell receptor β-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T.

CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma.

Purpose: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is effective against refractory or relapsed (R/R) B-cell lymphoma, but the efficacy is hindered by the existence of PD-1/PD-L1 pathway.

Patients And Methods: Here, we generated a novel anti-CD19 CAR-expressing PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR). We then conducted a phase Ib study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1 B-cell lymphoma.

Characterization of Microbiota in Cancerous Lung and the Contralateral Non-Cancerous Lung Within Lung Cancer Patients.

Background: The functional role of lung microbiota has attracted an accumulating attention recently, but the profile and functional role of the lung microbiota in patients with lung cancer remained largely unknown.

Methods: To evaluate the association of the microbiota with lung cancer, we performed comparative analysis of the lung microbiota using 16S rRNA amplicon sequencing approach in the paired bronchoalveolar lavage fluid (BALF) samples (paired samples from cancerous lung and the contralateral non-cancerous lung) from 50 cancer patients with unilateral lobar masses.

Results: We found that the relative abundance of phylum Tenericutes, its class Mollicutes, its order Entomoplasmatales, its family Spiroplasmataceae, and its genus was significantly increased in cancerous lung, but the relative abundance of phylum Bacteroidetes, its class Bacteroidia, and its order Bacteroidales was significantly decreased in cancerous lung.

Isolation of T cell receptor specifically reactive with autologous tumour cells from tumour-infiltrating lymphocytes and construction of T cell receptor engineered T cells for esophageal squamous cell carcinoma.

Background: T cell receptor-engineered T cells (TCR-Ts) therapy is a promising cancer treatment strategy. Nowadays, most studies focused on identification of high-avidity T cell receptors (TCRs) directed against neoantigens derived from somatic mutations. However, few neoantigens per patient could induce immune response in epithelial cancer and additionally many tumor-specific antigens could be derived from noncoding region.

Effectiveness of Intensive Endoscopic Screening for Esophageal Cancer in China: A Community-Based Study.

Evidence is required to evaluate the effectiveness of population-level endoscopic screening for esophageal cancer (EC). In this study, 5,632 permanent residents aged 25-65 years from 6 villages in Hua County, Henan Province, China, were defined as the screening cohort and were offered intensive endoscopic screening. Residents of all 914 remaining villages in Hua County were included as the control cohort, and age-sex standardization was used to calculate the expected numbers of EC and upper gastrointestinal (GI) tract cancer cases and deaths in the screening cohort.

T cell receptor β-chain repertoire analysis of tumor-infiltrating lymphocytes in pancreatic cancer.

Pancreatic cancer is lethal due to lack of perceptible symptoms and effective treatment methods. Immunotherapy may provide promising therapeutic choices for malignant tumors like pancreatic cancer. Tumor-infiltrating lymphocytes (TIL) in tumor mesenchyme could recognize peptide antigens presented on the surface of tumor cells.

Immediate and substantial evolution of T-cell repertoire in peripheral blood and tumor microenvironment of patients with esophageal squamous cell carcinoma treated with preoperative chemotherapy.

Preoperative chemotherapy could decrease tumor size and improve overall survival for esophageal squamous cell carcinoma (ESCC), and moreover, rational combination of chemotherapy and immunotherapy could increase likelihood of inducing an effective antitumor immune response. However, the immunologic impact of chemotherapeutic drugs originally chosen for cancer treatment due to the direct toxicity is poorly understood. We assess the effect of a combination of clinically approved chemotherapeutic drugs [paclitaxel-nedaplatin (PTX-NDP)] on T-cell receptor (TCR) repertoires of peripheral T cells and tumor-infiltrating lymphocytes (TILs) from five patients with primary ESCC.

TCR repertoire intratumor heterogeneity of CD4 and CD8 T cells in centers and margins of localized lung adenocarcinomas.

Intratumor heterogeneity (ITH) of T cell receptor (TCR) repertoire in different T-cell subsets and locations in lung adenocarcinomas was unclear. Here, we investigated percentages and TCR repertoire of freshly isolated CD4 and CD8 tumor infiltrating lymphocytes (TILs) in tumor centers and margins by flow cytometry on 80 tumor samples from 20 patients and high-throughput TCR sequencing on 27 and 25 samples of CD4 and CD8 TILs from seven patients. Our results demonstrated that amount and TCR repertoire diversity of CD4 TILs were significantly higher than those of CD8 TILs and moreover substantial ITH regarding amount and TCR repertoire of CD4 and CD8 TILs were observed.

Clonal distribution and intratumour heterogeneity of the B-cell repertoire in oesophageal squamous cell carcinoma.

Recent successes in tumour immunotherapies have highlighted the importance of tumour immunity. However, most previous studies to date have focused on T-cell immune response, although B cells are key players in the core immune network and are associated with T-cell immune response. Based on our previous study delineating T-cell receptor (TCR) repertoire in seven patients with oesophageal squamous cell carcinoma (ESCC), this study profiled the B-cell receptor (BCR) repertoire of multiple tumour regions, adjacent normal tissue, and blood from the same seven patients to reveal the characteristics of B-cell immunity and the relationship to TCR repertoire in ESCC patients.