The Stromal and Immune Landscape of Nasopharyngeal Carcinoma and Its Implications for Precision Medicine Targeting the Tumor Microenvironment

Abstract

The evolution of the tumor microenvironment (TME) is a cancer-dependent and dynamic process. The TME is often a complex ecosystem with immunosuppressive and tumor-promoting functions. Conventional chemotherapy and radiotherapy, primarily focus on inducing tumor apoptosis and hijacking tumor growth, whereas the tumor-protective microenvironment cannot be altered or destructed. Thus, tumor cells can quickly escape from extraneous attack and develop therapeutic resistance, eventually leading to treatment failure. As an Epstein Barr virus (EBV)-associated malignancy, nasopharyngeal carcinoma (NPC) is frequently infiltrated with varied stromal cells, making its microenvironment a highly heterogeneous and suppressive harbor protecting tumor cells from drug penetration, immune attack, and facilitating tumor development. In the last decade, targeted therapy and immunotherapy have emerged as promising options to treat advanced, metastatic, recurrent, and resistant NPC, but lack of understanding of the TME had hindered the therapeutic development and optimization. Single-cell sequencing of NPC-infiltrating cells has recently deciphered stromal composition and functional dynamics in the TME and non-malignant counterpart. In this review, we aim to depict the stromal landscape of NPC in detail based on recent advances, and propose various microenvironment-based approaches for precision therapy.

Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

“…Viral carcinogenesis-associated HCC and NPC are mainly caused by chronic hepatitis B virus (HBV) and Epstein-Barr virus (EBV), respectively. NPC, an endemic disease usually found in Southeast Asia and North Africa and etiologically linked to Epstein-Barr virus infection, represents a classic 'inflammatory tumor' that exhibits dense lymphocytes infiltration and high expression of PD-L1 [69]. Stromal cells are in close proximity to and in contact with NPC cells, which could make NPC microenvironment highly heterogeneous and immunosuppressive, preventing tumor cells from being infiltrated by drugs and immune attack, and promote tumor progression.…”

“…The exhausted T cells exhibit features associated with tertiary lymphoid structures (TLS) formation via B cell recruitment and increased abundance of suppressive regulatory T cell (Treg) in the microenvironment, where myeloid recruitment is an NPC-specific event. In addition, T cells entered the TIME and upregulated the activity of IFN-α and IFN-γ response pathways in macrophages, suggesting a potential anti-tumor capacity of these macrophages in NPC [56, 69,70]. In summary, the composition of TIME explained the mechanism of PD-1 inhibitor immunotherapy efficacy.…”

New insights into the tumour immune microenvironment of nasopharyngeal carcinoma

“…1 ). The three main cell lineages in the TIME are the T lymphocytes, B lymphocytes, and myeloid cells, which include myeloid-derived suppressor cells (MDSCs), macrophages, and dendritic cells ( Gong et al, 2021 ). Within the TIME, two functional subcategories of cells can be distinguished: immunostimulating cells, which facilitate the anti-cancer immune response, and immunosuppressive cells, which inhibit the anti-cancer immune response to promote tumour progression.…”

“…Its unique etiology is thought to be driven by a combination of genetic susceptibility, environmental factors, and association with the Epstein-Barr Virus (EBV) in most cases ( Wong et al, 2021 ). NPC is characterized by very high stromal and immune infiltration, which is likely due to proximity to lymphoid structures in the nasopharynx and the close association with EBV infection ( Gong et al, 2021 ). A key feature of NPC is the immune contribution to pathogenesis, where the immunosuppressive microenvironment provides a favourable environment for tumour cells ( Gong et al, 2021 ).…”

“…Chemoradiation is currently the standard of care for NPC, but recurrence occurs in approximately 20% of patients at which point the 5-year overall survival drops from 70% to 41% ( Howlett et al, 2021 ). Thus, significant focus has been placed on the use of novel strategies, in particular immunotherapy, in NPC to improve patient outcomes ( Gong et al, 2021 ). It has been shown that subtypes of NPC delineated by immune features of the tumour microenvironment can predict survival and response to immunotherapy ( Chen et al, 2021 ).…”