Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

Abstract

Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in-depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.

Keywords: clinical implications; immune mechanisms; soft tissue sarcoma; tertiary lymphoid structures (TLSs); tumor immune microenvironment (TIME).

FIGURE 1

Initiation and maturation of TLS. (A) The crosstalk between LTo and LTi initiates the formation of TLS. Related factors generate positive feedback, promote HEV formation, and recruit lymphocytes. (B) Dense lymphoid aggregate without FDCs or separate B/T cell compartments. (C) Primary follicular‐like TLS has B‐cell regions surrounding FDC and T‐cell regions surrounding HEV but lacks mature germinal centers. (D) Secondary follicle‐like TLS is characterized by the appearance of mature germinal centers, which marks TLS maturation.

FIGURE 2

Comparison of TLS in UPS and RMS. The difference in immune infiltration between UPS and RMS might determine their ICB response. Though their T cell densities are similar, UPS generates fewer TLS structures, thus its T cells are more diffused. TLS‐Tregs express high OX‐40 and 4‐1BB, which comes to targets for ICBs. These contribute to a complete response to ICB. T cells in RMS are restricted in TLS and suppressed by TAMs. They have been observed to cluster around abnormal tumor vascular. All the above results in depressed antitumor activity and ICB response.

FIGURE 3

Dual role of TLS in liposarcoma. Liposarcoma commonly occurs in the peritoneum. With the progression of liposarcoma, TLS switches from antitumor phenotype to protumor phenotype. At the early stage, TLS serves as the antigen‐presentation site between dendritic cells/tumor progenitor cells and T cells. It also recruits immune cells to enhance antitumor immunity. During late stages, TLS might act as a microniche that prevents tumor progenitor cells from being attacked and recruiting immunosuppressive cells. Thus, TLS contributes to tumor cell proliferation.

FIGURE 4

Main strategies to promote TLS formation and maturation. (A) The targets of ICB can be diverse, encompassing PD‐1 and CTLA‐4 on T cells, OX40 and 4‐1BB on Tregs, TIGIT on NK cells, and TIM4 on macrophages. Additionally, targeting enzymes such as IDO1 and FAK, applying TLR4 agonist or antiendogenous retrovirus therapy can also enhance the efficacy of ICB. (B) Adoptive cell therapies include ex vivo expansion of TIL, CAR‐T, CAR‐NK, and adoptive transfer B cells. (C) Tumor vaccine includes cell vaccine, nucleic acid vaccines, and peptide vaccine. (D) Kinase inhibitors, anti‐VEGF, Notch signal blocking, local cytokine injection, and continuous stimulation of LTα1β2 promotes HEV formation. HEV improves CD8⁺T and macrophage infiltration and ICB reactivity, which correlates with reduced tumor volume and prolonged survival.

FIGURE 5

Therapies related to TLS function. Several therapeutic strategies modulate TLS function. Immune therapy, including ICB, ACT, and tumor vaccine, might activate TLS and improve local immune infiltration. Kinase inhibitors, notch blockade, anti‐VEGF and STING agonist induces HEV generation. Chemotherapy, local injection of chemokines, and immunotoxin also induce TLS formation. Recent research advancements in TLS formation include epigenetic modifications, denervation, and promotion of venous development, which could be potential areas of treatment.