Mature tertiary lymphoid structures, close and ready to fight

Imagine there is a fire. For firefighters, being close to the flames and at the same time being trained and well-equipped are essential to handle the situation. Similar to a fire, cancer is a malignant lesion and the immune system wants to defeat it. But how similar are cancer and the immune system to fire and firefighters? How important is it to have a set of trained immune cells close to the tumor? Or is being close by enough? Does this also impact patients treated with therapies that help the immune system to respond to the cancer? A collaborative study involving different groups from France and the United States shed light on the answers to those interesting questions. These scientists recently published their research that discovered patients harboring cells of the immune system close to the tumor have a better response to a type of therapy that targets the immune system. Let’s learn about their research findings! 

Evoking a specific immune response against cancer

The immune system, the body’s own defense machinery, is the first line of defense against foreign substances and altered cells that could potentially lead to cancer. Some components of this machinery need to be trained against specific insults, like diseased and damaged cells  (i.e. cancer cells). The cells responsible for recognizing this insult and creating a specific immune response against it reside in specific organs known as lymph nodes. Lymph nodes are structures present throughout the body that work as filters for foreign invaders. They are mainly composed of specific immune cells such as dendritic cells, T cells and B cells, which are key players in the adaptive immune response. Dendritic cells exit the lymph node to patrol the neighboring environment, where they would identify a tumor as something foreign that should be eliminated. Then, they migrate back to the lymph nodes where they will train T cells to recognize this harmful substance and create a response against it. T cells are not the only immune cells capable of destroying this insult. T cells can also promote B cells to produce antibodies that will label specific insults to make the dangerous cell easily recognizable by the rest of the immune system. 

Tertiary lymphoid structures, an accumulation of immune cells close to the tumor

But dendritic cells, T and B cells do not just reside in lymph nodes. In the close neighborhood of some tumors, a similar structure that may contain dendritic cells, T and B cells has been observed, the so-called tertiary lymphoid structure (Figure 1). Tertiary lymphoid structures are similar in organization and function to lymph nodes, so they can foster immune response to foreign substances. Moreover, these structures can further facilitate the influx of immune cells into the tumor. Indeed chronic inflammation, such as cancer, can lead to the generation of these formations enriched from immune cells. However not all cancer types, not all cancer lesions and not all patients show the presence of these lymphoid structures and the reasons behind this are unclear. Generally speaking, when patients harbor tertiary lymphoid structures in the tumor microenvironment, they live longer. It seems like the closer to the insult, the better the body’s own defense machinery reacts and controls the diseased cells. 

Effector immune cells alone do not make a favorable environment to control tumor growth

Currently major cancer research is focused on the immune system to favor an antitumor response that benefits therapeutic outcome. In that regard, immunotherapy via harnessing the power of the immune system is a promising approach. But not all patients respond to this treatment and the reasons behind need to be identified. Do patients that do better upon immunotherapy harbor tertiary lymphoid structures? Is it important that this aggrupation of immune cells is close to the tumor? Is there any relation between the presence of tertiary lymphoid structures and survival of cancer patients treated with immunotherapy? 

To get answers to those questions, a group of researchers got access to human tumor biopsies from patients before starting immunotherapy treatment. Their study aim was to identify tertiary lymphoid structures, that is, an accumulation of immune cells in the vicinity of the tumor. Specifically, in the tumor biopsies they looked for the presence of effector cells (T and B cells) as an identification for tertiary lymphoid structures. They could identify a set of tumors that in its surroundings had those cells (“group with tertiary lymphoid structures”), and another set of tumors that did not have those cells (“group without tertiary lymphoid structures”) (Figure 1a, b). Interestingly, the presence or absence of this structure did not have an impact in patients’ survival upon immunotherapy treatment. Just having the effector immune cells close to the tumor was not enough to make the patients benefit from immunotherapy.

Figure 1. In some tumor surroundings, there may be an accumulation of immune cells. This aggrupation of immune cells is called tertiary lymphoid structure and its immune cell composition may vary from one tumor to another. a) Tumor without an accumulation of immune cells in its neighborhood. b) Tumor with tertiary lymphoid structures that are rich for T and B cells. b) Tumor with mature tertiary lymphoid structures. Mature tertiary lymphoid structures contain dendritic cells and T and B cells. Created with

At this point, the authors asked themselves: do all tumors harboring an accumulation of tertiary lymphoid structure look the same? Are there only T and B cells? Or is there any other cell type or something that could further distinguish them? Are also dendritic cells, the cells that initiate the adaptive response, in those aggregations? 

Looking closely in tertiary lymphoid structures with T and B cells, some samples had dendritic cells close to the effector T and B cells. Let’s remember that dendritic cells start the immune response and can thus activate T and B cells to make them respond to the cancer insult. Mature tertiary lymphoid structures is the name for the tertiary lymphoid structures rich in dendritic cells and T and B cells. Since the three cell types responsible for the adaptive response are present in mature tertiary lymphoid structures, they can be activated and act against the tumor (Figure 1c). Indeed this is exactly what was seen: tumors grew slower in those patients with mature tertiary lymphoid structures and thus patients’ survival was prolonged (Figure 2). In other words, immunotherapy could control tumor growth and prolong the life expectancy of those patients with an accumulation of training and trained immune cells close to the tumor. The presence of cells initiating the immune response and of fighting cells plays a key role in making patients respond to immunotherapy. 

Figure 2. Stimulating the body’s immune system has a more promising effect in tumor control and patient survival when patients have in the tumor neighborhood mature tertiary lymphoid structures. Mature tertiary lymphoid structures are an aggrupation close to the tumor rich in immune cells responsible for generating and executing an anti-cancer specific response. Created with

What we have learned from this study is the importance of the activation and well shape of the immune system. When this line of defense is properly present and active to function, its modulation with certain drugs that stimulate its function leads to a better control of patients’ tumor growth and ultimately to their survival. Gaining insight of what differentiates patients that have a good response to therapy to those who do not is important to identify the causes and look for alternatives. 

Coming back to the comparison of cancer and the immune system with fire and firefighters. It is not enough that firefighters (immune system) are close to the fire (cancer) to control it. The fireworkers also need to be well-equipped and trained to resolve the problem, and that is also important when it comes to our immune cells. 

This article summarizes work from: Vanhersecke, L., Brunet, M., Guégan, JP. et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat Cancer 2, 794–802 (2021).

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