Overcoming Barriers of Age to Enhance Efficacy of Cancer Immunotherapy: The Clout of the Extracellular Matrix

Owyong, Mark; Efe, Gizem; Owyong, Michael; Abbasi, Aamna J.; Sitarama, Vaishnavi; Plaks, Vicki

doi:10.3389/fcell.2018.00019

Cited by 20 publications

(27 citation statements)

References 72 publications

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“…Compared to CAR-T targeting CD19 for hematological malignancies, CAR-T targeting GPC3 for hepatocellular carcinoma did not show encouraging e cacy [22]. Various factors affect the therapeutic bene t of CAR-T on HCC, such as a poor tumor tissue microenvironment that limits proliferation and CAR-T cytotoxicity and the dense ECM which limits lymphocyte in ltration into tumor tissue [13,25].…”

Section: Discussionmentioning

confidence: 99%

“…Solid tumors have a more complex immunosuppressive microenvironment and there are many immunosuppressive cells and cytokines which inhibit the activation and survival of CAR-T cells within the tumor [11,12]. The dense extracellular matrix (ECM) also prevents CAR-T cells from in ltrating into solid tumors and can affect CAR-T cell activity [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…However, adding extra IL-7 during cultivation has no effect in vivo. It is di cult for T cells, including CAR-T cells, to penetrate the extracellular matrix and thus in ltrate the tumor [13,14]. Reports suggest that recombinant hyaluronidase rHPH20 has a greater clinical effect on ECM degradation, promoting lymphocyte in ltration into tumor cells [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

Liu

Wang

Jiang

et al. 2020

Preprint

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While CAR-T therapy has successfully treated hematological malignancies, it has proved sub-optimal for solid tumors. The main limitation is the inability of CAR-T cells to infiltrate and then proliferate within tumors. In this study, we co-expressed IL-7 and PH20, a type of hyaluronidase, with CAR targeting GPC3 (G3CAR-7×20) to address these issues. We found (G3CAR-7×20) exhibited better proliferation in vivo and in vitro than G3CAR, reduced the level of apoptosis after stimulation by tumor cells, and maintained the memory phenotype of CAR-T cells. G3CAR-7×20 also increased the ability of CAR-T cells to infiltrate tumor tissue. G3CAR-7×20 may significantly enhance the efficacy of CAR-T cells in solid tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

Liu

Wang

Jiang

et al. 2020

Preprint

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“…An established tumor contains not only tumor cells but also inflammatory cells, stromal cells, vasculature, and extracellular matrices, which are so called the tumor microenvironment (TME), and immune cells and immunoregulatory cells in the TME form the tumor immune microenvironment . Exploring the characterization of tumor immune microenvironment would be of great value to unravel the mechanism of silenced immune responses in tumor patients . Increasing evidences have confirmed that chemotherapy could influence the expression of immune checkpoints in tumor microenvironment .…”

Section: Introductionmentioning

confidence: 99%

“…8 Exploring the characterization of tumor immune microenvironment would be of great value to unravel the mechanism of silenced immune responses in tumor patients. 9 Increasing evidences have confirmed that chemotherapy could influence the expression of immune checkpoints in tumor microenvironment. 10 It has been reported that PD-1 and/or PD-L1 was upregulated after chemotherapy in leukemia and ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

Wang

Mao

Zhang

et al. 2019

J Oral Pathology Medicine

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Background Since the inhibitory immune checkpoint receptors have been described to benefit the OSCC patients clinically, it is unknown that whether their expression in tumor immune microenvironment (TME) can determine the clinical outcome in response to nimotuzumab therapy. Methods We examined the expression patterns of immune checkpoint receptors (including TIM‐3, LAG‐3, PD‐L1, and CTLA‐4) and an immunoregulatory enzyme called IDO in 36 OSCC patients during nimotuzumab therapy by immunohistochemistry. Then, we divided the recruited patients into clinical responders and non‐responders according to computed tomography (CT) scan and analyzed the relationship between the immunological parameters and clinical outcome. Results We observed that nimotuzumab therapy significantly increased the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 in the TME, and the expression of LAG‐3 and PD‐L1 before nimotuzumab therapy was inversely correlated with the overall survival. In clinical non‐responders, we found the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 was significantly increased during nimotuzumab therapy, and the expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 before nimotuzumab therapy was negatively correlated with the overall survival. However, in clinical responders, neither of those showed significant. Conclusions It suggests that these immune checkpoint receptors and IDO could be considered as biomarkers to reflect immune status in the tumor microenvironment during nimotuzumab therapy. Blockade of these immune checkpoint receptors might enhance nimotuzumab‐based cancer immunotherapy, thus potentially improving clinical outcomes of OSCC patients.

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Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

et al. 2023

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BackgroundThe understanding of the factors causing decreased overall survival (OS) in older patients compared to younger patients in lung adenocarcinoma (LUAD) remains.MethodsGene expression profiles of LUAD were obtained from publicly available databases by Kaplan‐Meier analysis was performed to determine whether age was associated with patient OS. The immune cell composition in the tumor microenvironment (TME) was evaluated using CIBERSORT. The fraction of stromal and immune cells in tumor samples were also using assessed using multiple tools including ESTIMATE, EPIC, and TIMER. Differentially expressed genes (DEGs) from the RNA‐Seq data that were associated with age and immune cell composition were identified using the R package DEGseq. A 22‐gene signature composed of DEGs associated with age and immune cell composition that predicted OS were constructed using Least Absolute Shrinkage and Selection Operator (LASSO).ResultsIn The Cancer Genome Atlas (TCGA)‐LUAD dataset, we found that younger patients (≤70) had a significant better OS compared to older patients (>70). In addition, older patients had significantly higher expression of immune checkpoint proteins including inhibitory T cell receptors and their ligands. Moreover, analyses using multiple bioinformatics tools showed increased immune infiltration, including CD4+ T cells, in older patients compared to younger patients. We identified a panel of genes differentially expressed between patients >70 years compared to those ≤70 years, as well as between patients with high or low immune scores and selected 84 common genes to construct a prognostic gene signature. A risk score calculated based on 22 genes selected by LASSO predicted 1, 3, and 5‐year OS, with an area under the curve (AUC) of 0.72, 0.72, 0.69, receptively, in TCGA‐LUAD dataset and an independent validation dataset available from the European Genome‐phenome Archive (EGA).ConclusionOur results demonstrate that age contributes to OS of LUAD patients atleast in part through its association with immune infiltration in the TME.

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Overcoming Barriers of Age to Enhance Efficacy of Cancer Immunotherapy: The Clout of the Extracellular Matrix

Cited by 20 publications

References 72 publications

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

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