Synthetic TILs: Engineered Tumor-Infiltrating Lymphocytes With Improved Therapeutic Potential

Jiménez-Reinoso, Anaïs; Nehme-Álvarez, Daniel; Domínguez-Alonso, Carmen; Álvarez‐Vallina, Luís

doi:10.3389/fonc.2020.593848

Cited by 21 publications

(18 citation statements)

References 86 publications

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“…Along with immunogenicity, studies have shown that inflammatory TIME can also increase patients' response to immunotherapy (33)(34)(35). Reports suggest that CD4+ and CD8+ TILs highly enriched in the tumor are related to a higher response rate after receiving immunotherapy (36,37). Intratumor tumor-associated macrophages (TAMs) can be reprogrammed under the action of TIME and can be switched between the M1 type for antitumor immunity and the M2 type for promoting tumor proliferation.…”

Section: Discussionmentioning

confidence: 99%

Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients

Wang

Lin

et al. 2021

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) effectively treat lung adenocarcinoma (LUAD) with fewer side effects. However, for LUAD patients, the lack of predictive markers for ICIs makes their clinical benefits less than ideal. Despite reports suggesting that a TTN (titin) mutation plays an important role in immunotherapy of solid tumors and gastric cancer, the relationship between the TTN mutation and LUAD immunotherapy has not been determined. We collected a LUAD cohort with whole-exome sequencing (WES) and immunotherapy prognosis. The ICI cohort was used to explore the relationship between TTN mutation status and prognosis. Then, the Cancer Genome Atlas (TCGA)-LUAD and Chen-LUAD cohorts were downloaded from the cbioportal website. We also used CIBERSORT, gene-set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA) to evaluate the proportion of immune cells and the degree of pathway activation in LUAD patients, respectively. DDR signaling pathways obtained from the Molecular Signatures Database (MSigDB), tumor mutation burden (TMB), and NAL were used to evaluate the immunogenicity of LUAD patients. In the ICI cohort, TTN-mutant (TTN-MT) had significantly longer overall survival (OS) than TTN-wildtype (TTN-WT) (P = 0.009). Univariate and multivariate COX models showed that TTN mutation status can independently predict immunotherapy prognosis. Notably, the results of tumor immune microenvironment (TIME) analysis showed that TTN-MT patients had inflammatory TIME, which showed enriched activated immune cells and higher immune scores. Immunogenicity analysis showed higher immunogenicity in TTN-MT patients, which indicated high levels of gene mutations in TMB, NAL, and DDR pathways. GSEA and ssGSEA results showed that TTN-MT was substantially enriched in chemokine secretion, inflammatory factor secretion, and antigen presentation. Some pathways related to immunosuppression and immune depletion were significantly downregulated. TTN-MT is associated with significantly prolonged OS in LUAD patients. Additionally, TTN-MT is related to high immunogenicity and inflammatory TIME, suggesting that TTN-MT may be a potential predictive marker for patients with LUAD to accept ICIs.

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Section: Discussionmentioning

confidence: 99%

Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients

Wang

Lin

et al. 2021

Front. Oncol.

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“…Tumor-infiltrating immune cells affect the efficacy of radiotherapy, chemotherapy, or immunotherapy, and thus the prognosis of cancer patients ( 30 – 32 ). We showed that GAD1, SPP1, and WFS1 were markedly positively correlated with diverse immune cells, including B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells in HCC.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of an 6-Metabolism-Related Gene Signature and Its Correlation With Immune Checkpoint in Hepatocellular Carcinoma

Ren

Liu

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) is a common malignant tumor with relatively high malignancy and rapid disease progression. Metabolism-related genes (MRGs) are involved in the pathogenesis of HCC. This study explored potential key MRGs and their effect on T-cell immune function in the tumor immune microenvironment to provide new insight for the treatment of HCC. Of 456 differentially expressed MRGs identified from TCGA database, 21 were screened by MCODE and cytoHubba algorithms. From the key module, GAD1, SPP1, WFS1, GOT2, EHHADH, and APOA1 were selected for validation. The six MRGs were closely correlated with survival outcomes and clinicopathological characteristics in HCC. Receiver operating characteristics analysis and Kaplan-Meier plots showed that these genes had good prognostic value for HCC. Gene set enrichment analysis of the six MRGs indicated that they were associated with HCC development. TIMER and GEPIA databases revealed that WFS1 was significantly positively correlated and EHHADH was negatively correlated with tumor immune cell infiltration and immune checkpoint expression. Finally, quantificational real-time polymerase chain reaction (qRT-PCR) confirmed the expression of WFS1 and EHHADH mRNA in our own patients’ cohort samples and four HCC cell lines. Collectively, the present study identified six potential MRG biomarkers associated with the prognosis and tumor immune infiltration of HCC, thus providing new insight into the pathogenesis and treatment of HCC.

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“…TIL products are heterogenous in terms of CD8 + /CD4 + T cell ratios and T-cell differentiation stage and can be impacted by tumor biology ( 164 ). For an endowment of resistance to tumor suppression and/or enhanced tumor homing, TILs can be genetically modified either using different types of vectors or via gene editing technologies ( 165 ).…”

Section: Multicellular Therapiesmentioning

confidence: 99%

Cell Therapy: Types, Regulation, and Clinical Benefits

2021

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Cell therapy practices date back to the 19th century and continue to expand on investigational and investment grounds. Cell therapy includes stem cell- and non–stem cell-based, unicellular and multicellular therapies, with different immunophenotypic profiles, isolation techniques, mechanisms of action, and regulatory levels. Following the steps of their predecessor cell therapies that have become established or commercialized, investigational and premarket approval-exempt cell therapies continue to provide patients with promising therapeutic benefits in different disease areas. In this review article, we delineate the vast types of cell therapy, including stem cell-based and non–stem cell-based cell therapies, and create the first-in-literature compilation of the different “multicellular” therapies used in clinical settings. Besides providing the nuts and bolts of FDA policies regulating their use, we discuss the benefits of cell therapies reported in 3 therapeutic areas—regenerative medicine, immune diseases, and cancer. Finally, we contemplate the recent attention shift toward combined therapy approaches, highlighting the factors that render multicellular therapies a more attractive option than their unicellular counterparts.

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Synthetic TILs: Engineered Tumor-Infiltrating Lymphocytes With Improved Therapeutic Potential

Cited by 21 publications

References 86 publications

Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients

Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients

Identification and Validation of an 6-Metabolism-Related Gene Signature and Its Correlation With Immune Checkpoint in Hepatocellular Carcinoma

Cell Therapy: Types, Regulation, and Clinical Benefits

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