B cells and CD4+ T cells co-activate killer T cells

B cells, we might think that it can secrete antibodies to neutralize pathogens

There are many studies on the role of Th1, Th2 and Th17 in tumor CD4 T cells

This recent study may refresh our inherent ideas

Recently, the team of Nikhil S.

They found that B cells and Tfh cells, which have been insignificant in tumor immunity, can actually increase CD8

▲Screenshot of newspaper homepage

Lung cancer is one of the tumors with the highest mortality, and lung adenocarcinoma is the most common subtype of lung cancer

The emergence of immune checkpoint inhibitors has changed the current status of lung cancer treatment, but only 20% of lung adenocarcinoma patients can benefit from it

In order to further improve the effectiveness of treatment, we need to have a deeper understanding of tumor-infiltrating immune cells

In order to understand which immune cells are infiltrated in lung adenocarcinoma, the researchers first analyzed the TCGA database and found that a variety of immune cells are enriched in lung adenocarcinoma tissue

In our traditional concept, the infiltration of CD8 T cells and myeloid cells (such as macrophages) in tumors is expected

However, surprisingly, the enrichment of B cells and CD4 T cells in these samples was more significant

Analysis of single-cell sequencing data further confirmed this finding

▲Assessment score of immune cell infiltration in lung adenocarcinoma samples (CIBERSORT algorithm)

GC B cells and Tfh cells play an important role in CP humoral immunity

▲The interaction between GC B cells and Tfh cells [3]

Researchers found that patients with high scores of B cells and Tfh cells in gastric cancer had better survival rates

The scores of gastric cancer B cells and Tfh cells are positively correlated with Th1 and CD8 effector T cell scores, suggesting that gastric cancer B cells and Tfh cells may play a role in promoting anti-tumor immune response in lung cancer

Next, the researchers used the mouse model to study this mechanism in depth

The researchers constructed a mouse model of lung adenocarcinoma transplanted subcutaneously called KP-HELLO
.

In this model, tumor cells express the B cell recognition antigen HEL, and T cells recognize the antigens GP33-43 and GP61-80
.

At the same time, the researchers used the KP-NINJA model that does not express HEL antigen but expresses GP33-43 and GP61-80 as a control
.

Flow cytometry found that compared with the KP-NINJA model, KP-HELLO can effectively induce tumor-specific Tfh cell and GC-B cell responses, suggesting that the recognition of antigens by B cells plays an important role in this process
.

Compared with wild-type mice, the growth of KP-HELLO tumors lacks B cells or Tfh cells is significantly enhanced in mice, while the growth of KP-NINJA tumors has no effect, which indicates that the response of Tfh cells and GC B cells is to inhibit KP -Nihao plays an important role in the development of tumors
.

▲In mice lacking Tfh cells (CD4-Cre Bcl6fl/fl) or B cells (uMT), the growth of KP-HELLO tumors was significantly enhanced

When it comes to suppressing tumors, the first thing everyone thinks of may be CD8 T cells
.

Sure enough, when Tfh cells or GC B cells are defective, the effector function of CD8 T cells will be significantly weakened
.

So, how do Tfh cells and GC B cells enhance the anti-tumor function of CD8 T cells?

The researchers concluded that the cytokine IL-21 may have played a key role in this process
.
IL-21 is a marker cytokine secreted by Tfh cells
.

Previous studies have shown that IL-21 can enhance the effector function of CD8 T cells [4]
.

Sure enough, the researchers found that there are a large number of Tfh cells expressing IL-21 in KP-HELLO tumors
.
In b-cell deficient mice, IL-21+ T cells were significantly reduced
.

In addition, IL-21+ T cells are also significantly lower in KP-NINJA tumors than KP-HELLO tumors
.
This indicates that the IL-21 signal of Tfh cells in tumors requires B cells and B cells to participate in the recognition of antigens
.

In addition, the researchers found that activated CD8 effector T cells express IL-21 receptor (IL21R) on the surface
.

After IL21R was knocked out, the infiltration of CD8 effector T cells in the tumor was significantly reduced, and tumor growth was also significantly enhanced
.

▲After il-21r is knocked out, tumor growth is significantly enhanced

So far, the research on its mechanism has been relatively clear
.
In order to make the study more rigorous, the researchers further explored the role of the interaction between Tfh and B cells in inducing anti-tumor immune responses
.

Previous studies have found that due to defects in the ability of T cells and B cells to help each other [5], mice lacking CD40/CD40L and ICOS/ICOSL cannot form GC B cells or mature Tfh cells
.

In this study, researchers found that defects in ICOS or CD40L can cause KP-HELLO tumors to grow faster
.
In addition, in the KP-HELLO tumor mice lacking tf-h cells, the GC B cell response was significantly reduced; while in the KP-HELLO tumor mice lacking B cells, or in the KP-NINJA tumor mice, the Tfh cell response The response is also significantly reduced
.

In these cases, the function of CD8 T cells was also significantly weakened, but infusion of tumor antigen-specific CD4 T cells can reverse these phenotypes
.

These results indicate that the interaction between Tfh and B cells plays an important role in inducing anti-tumor immune responses, but the presence of tumor-specific Tfh cells is sufficient to enhance the effector function of tumor-infiltrating CD8 T cells
.

▲General map of the organization

In summary, this study found that the interaction between tumor-specific CD4 T cells and B cells can induce the production of tumor-specific Tfh cells
.

Tfh cells can secrete IL-21 to enhance the anti-tumor effect of CD8 T cells
.
Role
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This discovery updates our understanding of CP on GC-B cells and Tfh cells, and may provide new ideas for tumor immunotherapy
.

references

1.
Cui C, Wang J, Fagerberg E, Chen PM, Connolly KA, Damo M, Cheung JF, Mao T, Askari AS, Chen S et al: Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses.
Cell 2021.

2.
Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S et al: Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC .
N Engl J Med 2020, 383(14):1328-1339.

3.
Nutt SL, Tarlinton DM: Germinal center B and follicular helper T cells: siblings, cousins ​​or just good friends? Nature Immunology 2011, 12(6):472-477.

4.
Zander R, Schauder D, Xin G, Nguyen C, Wu XP, Zajac A, Cui WG: CD4(+) T Cell Help Is Required for the Formation of a Cytolytic CD8(+) T Cell Subset that Protects against Chronic Infection and Cancer.
Immunity 2019, 51(6):1028-+.

5.
Crotty S: T Follicular Helper Cell Biology: A Decade of Discovery and Diseases.
Immunity 2019, 50(5):1132-1148.

B cells and CD4+ T cells join forces to activate killer T cells