Immunity Reveals Antitumor Mechanism of Tertiary Lymphoid Structure in Renal Cell Carcinoma Using 10x Genomics Visium FFPE Spatial Transcriptome Technology

Written by | The occurrence and development of cancer is a complex process involving the accumulation of mutations in cells, which can cause cells to escape "life and death control"; on the other hand, these mutations can also lead to tumor-specific antigen expression, which triggers innate and acquired antitumor immune responses to eliminate tumor cells
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Traditionally, anti-tumor immune responses are thought to originate in secondary lymphoid organs, such as dendritic cells that migrate to secondary lymphoid organs after receiving antigens at the tumor to present antigens to T cells
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However, through the study of infiltrating lymphocytes in tumors, it was found that there was a correlation between them and the survival of patients, which not only proved the important role of the microenvironment in tumor control, but also found that there is actually a group of immune cells aggregated at the tumor site.
A tertiary lymphoid structure (Tertiary lymphoid structures, TLS below, the corresponding concept is primary lymphoid structures/organs and secondary lymphoid structures/organs), and multiple studies have also revealed the existence and heterogeneity of tertiary lymphoid structures associated with a good prognosis
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Figure: Tertiary lymphoid structure, from 2019 Nature Reviews Cancer The tertiary lymphoid structure can be seen as a lymphocyte aggregate built on a network of fibroblasts, including two important structural areas - the T cell area (as above Figure, T cell zone) and (follicular) B cell zone
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Mature tertiary lymphoid structures are defined as the presence of a germinal center (GC), which contains T follicular helper cells and follicular dendritic cells, and is closely associated with B cells
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Subsequent studies have also identified mature tertiary lymphoid structures, rather than GC-free tertiary lymphoid structures, that correlate with prognosis in a variety of cancers
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The germinal center is an important place for the generation of memory B cells and long-lived plasma cells, among which the long-lived plasma cells can secrete high-affinity antibodies, so another study revealed that the tertiary lymphoid structure and B cells jointly affect the prognosis of cancer and the immune response.
The effect of checkpoint therapy
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However, it is not clear which B cells and plasma cells play an important role here.
On February 28, 2022, the team of Wolf Herman Fridman of the Sorbonne University in France published an article in Immunity.
Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer, using 10x Genomics Visium FFPE spatial transcriptome technology to discover Tertiary lymphoid structures (TLS) in renal cell carcinoma are important sites for B cell maturation and differentiation into plasma cells (also called effector B cells), and IgG+ plasma cells are associated with immune checkpoint inhibitor treatment response and progression-free survival in patients showing a positive correlation
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The researchers selected tumor samples from 130 patients with naïve renal cell carcinoma in 3 centers, including 59 patients who underwent PD-1 inhibitor Nivolumab (N group, 18 cases)/Nivolumab combined with CTLA-4 inhibitor Ipilimumab ( NI group, 35 cases)/VEGFR inhibitor (TKI group, 6 cases) treatment
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All 130 tumor samples were analyzed using spatial imaging technology, of which 24 tumor samples consisted of 12 frozen tissues (8 TLS+, 4 TLS-), 12 FFPE sections (10 TLS+, 2 TLS-).
10x Genomic Visium spatial omics analysis was performed to analyze its spatial structure.
The following figure shows three types.
ABC is the spatial transcriptome of frozen tumor tissue containing tertiary lymphoid structure, and DEF is the spatial transcriptome of FFPE tumor tissue containing tertiary lymphoid structure.
, GHI is the spatial transcriptome of frozen tumor tissue without tertiary lymphoid structure
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Analysis of these spatial omics revealed a correlation of TLS with B-cell, T-cell, and fibroblast characteristics
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The researchers then performed a detailed analysis of transcriptional signatures combined with spatial information and found that in TLS+ tumors, plasma cells expressing IGHG1 and IGHA1 were located near TLS and spread along fibroblasts
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Given that this co-localization of plasma cells with different mature subtypes of B cells implies that B cells develop acquired immunity, the researchers analyzed B cell receptors and found that TLS mediates B cell maturation and cloning in situ Sexual amplification
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So how do these IGHG1 and IGHA1-expressing plasma cells relate to tumor cells? The researchers found that tumor cells could bind to IgG antibody, and the tumor cells bound to it had significantly higher apoptosis than the unbound state, and were accompanied by higher infiltration of CD68+ macrophages
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To assess the relevance of these findings to tumor immune checkpoint inhibitors, the researchers looked at the N group (16 of 18 patients) and the NI group and found that patients in the group with high IgG expression in tumor tissue had significantly longer survival
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In conclusion, this study utilizes the 10x Genomics Visium FFPE Spatial Transcriptome Solution to demonstrate our understanding of in situ B cell differentiation in the tertiary lymphoid structure of the tumor microenvironment, revealing that IgG and IgA plasma cells, especially IgG-secreting plasma cells, play a role in anti-tumor The role of tumor immune response provides new ideas for our understanding of cancer immunotherapy
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Link to the original text: https://doi.
org/10.
1016/j.
immuni.
2022.
02.
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