Selective homing of phenotypically lytic cells within nasopharyngeal carcinoma biopsies: Numerous CD8‐ and CD16‐positive cells in the tumor

Lakhdar, Mohamed; Aribia, M.H. Ben; Maâlej, M.; Ladgham, A.

doi:10.1002/ijc.2910480111

Cited by 15 publications

(6 citation statements)

References 20 publications

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“…Similarly, the percentages of the tumor-infiltrating T cells were also reduced, as demonstrated using another NPC-PDX ( Figure S4A-K). Consistent with the primary tumor, T cells were also the major immune cell subset in the NPC-PDX, albeit the tumor-infiltrating macrophages and NK cells accounted for around 5% in our model [28,29]. Hence, the expressions of immune checkpoint receptors on the cytotoxic T lymphocytes were further examined.…”

Section: Tumor-infiltrating T Cells Display Exhausted Phenotypesmentioning

confidence: 91%

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Liu

Fong

Tan

et al. 2020

Cancers

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Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein–Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein–Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-γ) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-γ towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients.

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Section: Tumor-infiltrating T Cells Display Exhausted Phenotypesmentioning

confidence: 91%

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Liu

Fong

Tan

et al. 2020

Cancers

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“…The appearance of a malignant process producing several immunogenic viral proteins within a context of local inflammation and heavy leukocytic infiltration is one major paradox of NPC pathogenesis. Moreover, another important biologic feature of NPC is the presence of a massive population of tumor-infiltrating lymphocytes (TILs) in the primary tumor [6-8]. Our previous study indicated that the frequencies of different TIL subsets, including CD8 + , FOXP3 + , and IL-17-producing TILs, have prognostic value in NPC patients.…”

Section: Introductionmentioning

confidence: 99%

Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma

et al. 2014

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Tumor-derived exosomes contain biologically active proteins and messenger and microRNAs (miRNAs). These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape. Here, we isolated 30-100 nm exosomes from the serum of patients with nasopharyngeal carcinoma (NPC) or the supernatant of TW03 cells. Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients (P < 0.05). TW03-derived exosomes impaired T-cell function by inhibiting T-cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro. These results are associated with decreases in ERK, STAT1, and STAT3 phosphorylation and increases in STAT5 phosphorylation in exosome-stimulated T-cells. TW03-derived exosomes increased the proinflammatory cytokines IL-1β, IL-6, and IL-10 but decreased IFNγ, IL-2, and IL-17 release from CD4+ or CD8+ T-cells. Furthermore, five commonly over-expressed miRNAs were identified in the exosomes from patient sera or NPC cells: hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p, and hsa-miR-1908. These over-expressed miRNA clusters down-regulated the MARK1 signaling pathway to alter cell proliferation and differentiation. Overall, these observations reveal the clinical relevance and prognostic value of tumor-derived exosomes and identify a unique intercellular mechanism mediated by tumor-derived exosomes to modulate T-cell function in NPC.

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“…In addition, a large number of tumor infiltrating lymphocytes (TIL) are found around the NPC tumor tissues [5-8]. The majority of the cells in the tumor are reactive and consist predominantly of T cells with variable numbers of other inflammatory cells [9]. The presence of TIL correlates with an better prognosis in patients with several types of cancer, and each T lymphocyte subset has a unique role in the antitumor response [10-14].…”

Section: Introductionmentioning

confidence: 99%

Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways

Zhang

et al. 2010

Mol Cancer

125

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BackgroundIncreasing amounts of evidence indicate that tumor infiltrating lymphocytes (TIL) are correlated with the prognosis of cancer patients. This study focuses on the association between the densities of tumor infiltrating cytotoxic T lymphocytes (CTL), activated CTL, regulatory T lymphocytes (Treg) and Th17 lymphocytes, and the prognosis and clinicopathological features of nasopharyngeal carcinoma (NPC) patients.ResultsDouble immunohistochemical staining was performed in 106 biopsy specimens from newly diagnosed NPC patients. Prognostic values of infiltrating lymphocyte densities were evaluated by Kaplan-Meier analysis and Cox regression. The density of CD8+ TIL was positively correlated with lymph node metastasis, while the density of Foxp3+ TIL was negatively associated with T stage (P < 0.05). For survival evaluation, the density of Foxp3+ TIL or Foxp3+ TIL combined with GrB+ TIL together was associated with better overall survival (OS) and progression-free survival (PFS) (P < 0.01) in all patients and in the patients with late-stage diseases (Stages III and IV, P < 0.01). Meanwhile a low density of CD8+TIL or high ratio of FOXP3+TIL to CD8+TIL was correlated with better PFS in early stage patients (Stages I and II, P < 0.05). No significant association was found between IL-17+ TIL and clinicopathological characteristic or survival of NPC patients.ConclusionsOur study identifies for the first time the tumor infiltrating Foxp3+ TIL as an independent favorable factor in the prognosis of NPC patients, especially for the patients with late-stage diseases.

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Selective homing of phenotypically lytic cells within nasopharyngeal carcinoma biopsies: Numerous CD8‐ and CD16‐positive cells in the tumor

Cited by 15 publications

References 20 publications

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma

Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways

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