Reprogramming of sentinel lymph node microenvironment during tumor metastasis

Abstract

Metastasis is a major cause of death in patients with cancer. The two main routes for cancer cell dissemination are the blood and lymphatic systems. The underlying mechanism of hematogenous metastasis has been well characterized in the past few decades. However, our understanding of the molecular basis of lymphatic metastasis remains at a premature stage. Conceptually, cancer cells invade into lymphatic capillary, passively move to collecting lymphatic vessels, migrate into sentinel lymph node (SLN;, the first lymph node to which cancer cells spread from the primary tumor), and enter the blood circulatory system via the subclavian vein. Before arriving, cancer cells release specific soluble factors to modulate the microenvironment in SLN to establish a beachhead for successful colonization. After colonization, cancer cells inhibit anti-tumor immunity by inducing the recruitment of regulatory T cell and myeloid-derived suppressor cells, suppressing the function of dendritic cell and CD8+ T cell, and promoting the release of immunosuppressive cytokines. The development of novel strategies to reverse cancer cell-triggered SLN remodeling may re-activate immunity to reduce beachhead buildup and distant metastasis. In addition to being a microanatomic location for metastasis, the SLN is also an important site for immune modulation. Nanotechnology-based approaches to deliver lymph node-tropic antibodies or drug-conjugated nanoparticles to kill cancer cells on site are a new direction for cancer treatment. Conversely, the induction of stronger immunity by promoting antigen presentation in lymph nodes provides an alternate way to enhance the efficacy of immune checkpoint therapy and cancer vaccine. In this review article, we summarize recent findings on the reprogramming of SLN during lymphatic invasion and discuss the possibility of inhibiting tumor metastasis and eliciting anti-tumor immunity by targeting SLN.

Construction of CpG Delivery Nanoplatforms by Functionalized MoS2 Nanosheets for Boosting Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

“…In addition to the tumor microenvironment, the immune status of lymph nodes in the tumor‐draining area and spleen are also tightly related to the antitumor effect, especially for post‐treatment tumor relapse and metastasis. [ 52 ] The results revealed that the maturation of DCs (CD11c + CD40 + , CD11c + MHCII + , and CD11c + CD80 + CD86 + ) in the tumor‐draining lymph nodes was significantly higher in the CpG@ M M ‐ P L ‐treated mice than those mice injected with saline and CpG alone ( Figure A–D and Figure S16, Supporting Information). Moreover, flow cytometry analysis of spleen single‐cell suspension demonstrated that CpG@ M M ‐ P L treatment relatively promoted the IFN‐ γ , TNF‐ α , granzyme B, and perforin generation of CD8 + T cells in the spleen compared to those in the saline and CpG groups, meaning the tumor‐killing functions of CTLs in the spleen were extremely elevated after administration of the nanoplatforms (Figure 6E–H).…”

Roles of circRNA dysregulation in esophageal squamous cell carcinoma tumor microenvironment

“…Here, we summarize the biological functions and clinicopathological features of the aberrantly expressed circRNAs in ESCC (Table 1). ESCC mainly carries out distant metastasis through the lymphatic system, causing patients to lose the opportunity for early surgery, and is directly related to poor prognosis (118)(119)(120). High expression of circ_0048117, circ_0001093, circ_0000705, and circHIPK3 are closely related to lymph node metastasis and the TNM stage of ESCC (84, 88,90,95).…”

Focused Ultrasound‐Responsive Nanocomposite with Near‐Infrared II Mechanoluminescence for Spatiotemporally Selective Immune Activation in Lymph Nodes

“…[7,8] Therefore, it is of great significance to regulate the immune response of LN for and inhibit the spread of disease-causing organisms. [9,10] Nanomaterials are designed to load immune agonists, which could activate immune cells in lymph nodes to initiate an immune response. [11][12][13][14][15] However, several challenges remain in achieving spatiotemporal control of immune regulation of LN.…”

“…For example, sentinel LN are important metastasis pathway for cancer cells [7,8] . Therefore, it is of great significance to regulate the immune response of LN for and inhibit the spread of disease‐causing organisms [9,10] . Nanomaterials are designed to load immune agonists, which could activate immune cells in lymph nodes to initiate an immune response [11–15] .…”