Tertiary lymphoid structures Flashcards
What are tertiary lymphoid structures (TLS)?
They are structures within non lymphoid organs that share similar anatomy to secondary lymphoid organs and show accumulation of leukocytes. They can form separate T and B cells compartments, contain germinal centres with follicular DCs. They can direct various B and T cell responses like antibody generation, affinity maturation, class switching and clonal expansion
Where tertiary lymphoid structures usually develop?
At the site of infection, malignancy or autoimmunity.
Are they connected to good or bad prognosis?
It depends, in autoimmunity they are connected to poor prognosis but in malignancy they are connected to better prognosis.
What inflammatory diseases have been connected to the presence of TLS?
- RA
- Hashimoto’s
- MS
- H.pylori gastritis
- Ductal breast carcinoma
What is another name for tertiary lymphoid structures?
Ectopic lymphoid structures (ELS)
How are TLS formed?
Formation of TLS is driven by communication between local stromal cells, tissue-specific resident mononuclear cells and infiltrating immune cells. The cell types associated with this process are potentially:
- lymphoid tissue inducer cells (LTi cells)
- IL-17 secreting CD4 T cells
- Tfh cells
These cells are attracted to inflammatory sites by chemokine signals (CXCL13, CCL21) and resident stroll cells contribute to organisation of these structures. IL-7 and LTa1B2 regulate chemokine expression for further T and B cells recruitment, arrangement and control of angiogenesis. Follicular DCs present antigens, Tfh cells provide support and survival signals to B cells. TLS have similar action like germinal centres (Pitzalis 2014)
What are targets for TLS in immunotherapy?
- Antibody targeting inflammatory cytokines like IL-17 or IL-7
- lymphocyte depletion therapy
- co-stimulatory blockade (blockade of CD40 or ICOS)
- Antibody to homeostatic cytokines (CXCL13, CCL21)
- Treg therapy or treatment with anti-inflammatory cytokines like IL-27
(Jing 2016)
What is the role of fibroblasts in TLS?
Patients treated with rituximab lost TLS but once therapy was stopped, TLS returned. This was caused by stroll cells producing CXCL13 and IL-7. There was a fibroblasts population identified which produce IL-7, CCL19 and CCL21 attracting B cells population. These fibroblasts are important for TLS as in their absence TLS did not form. These fibroblasts can be a potential therapeutic target (Barone 2016)
For targeting TLS in autoimmunity should we target only one target or more?
Formation of TLS is a complex process and most likely there need to be a combination of targeting both stromal and immune cells
Are TLS in cancer always beneficial?
No, TLS role in cancer depends on their location within the tumour. It has been shown that if TLS is in the tumour it is associated with better prognosis however if TLS is adjacent to the tumour it is associated with tumour progression (Sautes-Fridman 2019)
What is a correlation between immune checkpoint blockade and TLS?
Patients given ICB who respond well had TLS structures present in the tumour. There is a potential in the future to induce TLS as treatment in combination with ICB for malignancies (Sautes-Fridman 2019)
