Abstract
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.
Highlights
Nasopharyngeal carcinoma (NPC) is characterized by distinct geographical distribution, which is highly associated with chronic infection of Epstein–Barr virus (EBV) [1]
Most nasopharyngeal carcinoma (NPC) cases belong to the non-keratinizing subtype that is highly correlated with EBV infection, where the susceptibility to the infection is likely affected by dietary components and smoking [5]
In our humanized mouse NPC-patient-derived xenograft (NPC-patient-derived xenografts (PDX)) model, the tumor-infiltrating CD8+ T cells expressed higher of programmed death1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), as well as lymphocyte-associated gene 3 (LAG3), and these exhausted phenotypes might hinder the anti-tumor levels of PD-1 and CTLA-4, as well as LAG3, and these exhausted phenotypes might hinder the antiefficacy of immune checkpoint blockade (ICB) by suppressing their cytotoxicity and cytokine-producing capability
Summary
Nasopharyngeal carcinoma (NPC) is characterized by distinct geographical distribution, which is highly associated with chronic infection of Epstein–Barr virus (EBV) [1]. Several patient-derived xenografts (PDX) from primary or metastatic NPC have been established and characterized in athymic nude mice [18,19], while more recently another few EBV-positive PDX have been successfully propagated in non-obese diabetic-severe combined immunodeficiency (NOD scid) mice [20]. These in vivo models provide limited information to immune-oncology research due to the absence of human immune system.
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