Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

Abstract

Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin®) and rituximab (Rituxan®)) and the first approved cancer vaccine, Provenge® (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

B Lymphocytes and Cancer: A Love–Hate Relationship

“…The numbers of TLOs correlate directly with positive outcomes in both human disease and mouse models [106–108]. In fact, the presence of B cells in high density within TLOs is a prognostic marker predicting longer patient survival in lung cancer [109].…”

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

“…TLS are distinct from primary and secondary lymphoid organs as they do not form during embryonic development and instead can originate in any non-lymphoid tissue that has been subject to prolonged/chronic inflammation (Aloisi & Pujol-Borrell, 2006). TLS express chemokines including CCL19, CCL21, and CXCL13 that recruit naive and effector CD4 + and CD8 + and memory CD4 + T cells, B cells, and NK cells to sites of inflammation (Erica M Pimenta & Barnes, 2014). The primary cell populations found within TLS are dendritic cells (DC), B cells, and naive and memory T cells (Wolf Herman Fridman, Pagès, Sautès-Fridman, & Galon, 2012).…”

“…These structures allow for activation, expansion and differentiation of tumor antigen-specific B and T cells within the tumor itself, leading to more effective anti-tumor immune response even in the absence of therapeutic intervention (de Chaisemartin et al, 2011; Erica M Pimenta & Barnes, 2014). In melanoma, a 12-gene signature has been characterized that predicts both the presence of TLS within a tumor and increased survival.…”

Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

“…In most cancers, TLS are associated with a favorable prognosis [15][16][17]. It must be noted that TLS are also speculated to be a mere bystander effect of inflammation within the TME and not as an active participant in mediating anti-tumour immune response in certain cancer sites [12,18]. Interestingly, a recent study on hepatocellular carcinoma describes these TLS as micro niches supporting tumour cell growth and survival [19].…”

“…Recently TLS have gained attention due to their associations with prognosis in certain cancers [12][13][14]. Intra-tumoural TLS have been widely reported in colorectal and ovarian cancers and are suggestive of ongoing B cell expansion.…”