Tertiary Lymphoid Structures and B cells: Clinical impact and therapeutic modulation in cancer

Abstract

Tumor type Nb of cases TLS detection % of cases featuring TLS or high expression of TLS marker Prognostic value Correlation between TLS maturation and recurrence Predictive impact of TLS Ref Breast 248 IHC 42% Favorable in HER2+ tumors (39) Breast 146 IHC HEV or DC-Lamp 33% Favorable (40, 41

Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity

“…The formation of active TLS at the tumor site can be interpreted as helping to position specific cellular interactions necessary for the generation of antigen-specific humoral and cytotoxic immune responses in a microenvironment protected from direct tumor-mediated suppression. This view is consistent with survival studies in numerous cancer types showing that TLS are a favorable biomarker (6), which together with the recent work linking them to immunotherapy responsiveness, highlights their importance in antitumor immunity. Importantly, the specific immune cell subpopulations and gene expression patterns associated here with active TLS, lacking in tumors with inactive TLS or TIL but no TLS, are clearly linked with positive clinical outcomes.…”

“…The generation of immune responses at the tumor site, currently quantified by the morphological evaluation of stromal TIL(2), have been linked with positive clinical outcomes in many solid tumor types including BC (32,33). Cumulative evidence advocates that specific cellular interactions and soluble factors, reflecting effective antitumor immune responses, come together when TIL are organized in TLS (5,6). Three key gene expression studies published last year highlighted the importance of TLS and TIL-B in predicting responses to immunotherapy and survival in patients with sarcoma (12), melanoma(10, 11) and renal cell carcinoma (11).…”

“…Isolated TIL are more frequently observed in the tumor bed while TIL accumulations are commonly located in the stroma as aggregates or tertiary lymphoid structures (TLS)(4). TLS have been detected in a wide range of solid tumors with evidence supporting their functionality as mini-lymph nodes at these chronic inflammatory sites (5,6). An increasing number of studies, including our work on BC, report that tumor-associated TLS with active germinal centers (GC) are linked with positive clinical outcomes (4,(7)(8)(9) and responses to immunotherapy (10)(11)(12).…”

Tertiary Lymphoid Structures as a Predictive Biomarker of Response to Cancer Immunotherapies

“…Whether different antigen presenting cell populations support particular subsets of T cells, act at different stages of immune response to tumours or play interchangeable roles, remains to be seen. Additionally, B cells may support CD8 T cells indirectly via CD40-CD40L interactions with CD4+ T follicular helper cells, which would then provide enhanced help to effector T cells ( 53 ).…”

Inducible Tertiary Lymphoid Structures: Promise and Challenges for Translating a New Class of Immunotherapy

“…This is best exemplified in hepatocellular carcinoma (HCC) (35), and suggests that while TLS represent an integral part of the anti-tumor immune response, their function is likely influenced by a number of contextual signals, including those afforded by local stroma, secreted inflammatory factors, other resident immune populations, local vasculature, and epithelium (36). This may also indicate that different types of TLS exist that are susceptible to immune polarization or can even serve an immune suppressive role depending on and subsequent to microenvironmental context (37). This review will focus on approaches that can be taken to artificially induce TLS as a novel immunotherapy or as a means of augmenting immunotherapies.…”