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Furthermore, B cells appear to be unevenly distributed in different cancers and subtypes, which are important components of the entire cancer immune system. For example, B cells have lower infiltration in esophageal squamous cell carcinoma than colon cancer (coad) and skin melanoma (skcm). An immune landscape study of squamous cell carcinoma in the head and neck showed that hpv                                                                                                                                                                                                                

Outwardly size, the composition of tilbs will also change during the longitudinal progression of the tumor, promoting or inhibiting the development of the tumor. B cells in early CRC tumors are most likely pre-b-like cells expressing tumor suppressors, while in advanced CRC tumors, they are often PCs. Compared with primary colorectal cancer, B cells are significantly reduced in liver metastasis, and immunosuppression TME.na?ve-like decreases in B cells and increase in PCs in advanced NSCLC, indicating a poor prognosis. Increased expression of humoral immune genes (such as ighg1) is observed in patients with cirrhosis, which indicates a compensatory increase in humoral immunity before tumor formation. Therefore, when the expression of humoral immune genes suddenly decreases, there may be a risk of tumor development.

So far, the single-cell immune profiles of many cancers have been mapped, such as melanoma, breast cancer, lung cancer and colorectal cancer, but they are mainly concentrated in T cells or MDSSCs. Single-cell research in pan-cancer focuses on the heterogeneity and function of T cells, rather than B cells, because they are high in TME. However, B cells, as an important part of adaptive immunity, are often overlooked due to their small proportion, which is also the reason for the missing part of the tumor immune profile. In addition, the differences between B cells of different molecular subtypes and dynamic changes in the development of tumors have made researchers need to conduct horizontal and vertical research on B cells, which is also lacking in current studies. Especially in immunotherapy studies, samples need to be collected from multiple time points, dynamically monitored B cells, and observed the treatment response.

B-cell subpopulations in tumors

Generally, according to the differentiation process, B cells can be divided into naive B cells, mbcs and ascs, each with different phenotypes and functions in TME (Table 2). When mapping cancer immune cells, due to the low proportion of B cells in specific cancers, they are usually divided into cd19cd20b cells and cd138sdc1pc. ScRNA-seq analysis for til-b reduces the size of these cells to higher resolution, resulting in a more different population of B cells. mbcs are usually divided into exchange mbc(igd-) and non-exchange mbcs(igd). In addition, Ascs can also be divided into pc(cd138) and plasmablasts (pbs) (cd138

-). Relying on the scRNA-seq platform, some subpopulations can also be determined by their highly expressed specific genes, rather than traditional B-cell classification. For example, follicular B-cells (cd19cd20), gc    B-cells (lrmpcd38), activated B-cells (cd71cd10-ki67) and interferon-induced B-cells (ifitm1ifi44l). In summary, the objective diversity of B-cell subpopulations in different tumors and the subjective individualization methods of single-cell analysis together lead to the diversity of the definition of the til-B subpopulations. Therefore, appropriate and accurate definition of B-cells that meet the research purpose has proposed a higher level of biological knowledge for researchers.

tertiary lymphoid structure

TLS is a cluster of lymphocytes located in the core or marginal region of the tumor, mainly including GC with FDC and T cell regions with mature DC. TiL-B is induced to differentiate by ACP and TFH cells, mediate anti-tumor function and achieve in situ tumor destruction (Figure 3). Due to the importance of TLS in antigen presentation, activation of B cells, increasing cytokine signaling and promoting tumor-related antibodies release, the role of TLS on immune response is very significant. In several studies, TLS has been shown to be positively correlated with the survival rates of melanoma patients, lung cancer patients and breast cancer patients. Interestingly It is that TLSs in the inflammatory areas near tumors may promote metastasis and recurrence of certain cancers. The localization method of TLS mainly relies on hℑimage;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;image;im

Helmink et al. classified 1760 B cells in the melanoma neoadjuvant IB test cohort and concluded that the presence of TLS is closely related to IB response and may be a sign of higher overall survival. Compared with non-responders, responders had more abundant B-cell infiltration from baseline, which is predictive. In addition, compared with non-responders, responders had increased clonal counts and BCR diversity. It is worth noting that another melanoma cohort study found that T cells in TLS were mainly CD4T cells, not CD8T cells, which experienced antigen presentation and expressed the survival molecule BCCL-2. Therefore, the presence of TLS-bound CD8T cells may be the best marker for predicting the immune response and overall survival in these patients.

In addition, Petitprez et al. established a sarcoma immune classification based on TME and found that patients with grade E (i.e., high expression of immune populations, especially B-line) respond best to ICB and have the highest survival rate. A common phenomenon is that tumors with TLS richness have more CD8T cell infiltration. One possible explanation is that B cells guide CD8T cells to recognize tumor neoantigens. These CD8T cells can be predepleted and pd-1, which makes ICB play a role in these TLS-rich tumors. In short, TLS is where ABC and CD8T cells produce anti-tumor immunity, which can convert immunosuppressed tumors into immunogenic tumors, creating an opportunity for ICBs to maximize anti-tumor effects. Therefore, induction of TLS by targeting cytokines such as light that targets tumor blood vessels combined with immunotherapy may prolong the patient's survival.

Memory B cells

According to whether CSR occurs during the interaction between MBCS and TFH cells, MBCS is divided into non-exchange MBCS      (igd) and exchange MBCS      (igd-). Double-negative MBS is detected in some autoimmune diseases       (cd27-igd-) recently found in NSCLC and is negatively correlated with the number of switched MBCSs, which may be a depleted B-cell subtype. It is worth noting that in humans, it is noted that In TNBC-like tissues, igh lineage analysis showed that cd27-atypical mbs had the highest intra-cluster diversity, suggesting more shms. It has also been reported that the number of double-negative til-bs is related to Treg cell phenotype (foxp3     CD4                                                                                 �

Non-exchange mbcs are also called early storage or GC B cells. They do not experience CRS and have the potential to differentiate into traditional mbs or longevity PCs. In GC, non-switched mbs provide MBs to TFH cells and promote their maturation. Lu et al. discovered the Icoslcd20 that appears after neoadjuvant chemotherapy in human breast cancer tissues. Using B cell-specific deletion mice, it was found that Icosl in B cells increases by inducing T cell activation.

Strong anti-tumor immunity. Similarly, antigen presentation functions of til-bs                                                                                                                                                                                                                                                   �

But the B cells of the non-responder are mainly Na?ve   B cells, which highlights the role of MBCS in inducing ICB response. Wieland et al. isolated three groups of B cells from hpv                                                                                                                                                                                                                                 

,After preoperative chemotherapy, an activated immune-activated B-cell that is upregulated by immunocostimulatory and MHC molecules replaces B-cells with previously lower activation. PDAC patients have infiltrated switched MBCSs early in the disease progression. It is worth noting that the exploration of MBCSs in TME focuses on their two main functions, antigen presentation and antigen-specific memory, which allow the binding of humoral and cellular immunity. However, most studies focus on the MBCS group rather than more detailed classification, which ignores the different functions between subgroups.

Antibody secretion cells

Asc can be divided into PBS and PC. GC cells are committed to differentiating into PC, downregulating CD23 expression and il-4 signaling, and developing into pre-PBS to adapt to their new secretory functions. PBS refers to the transient differentiation between B cells after GC and mature PCs with proliferation and antibody production ability. However, there is evidence that PBS is also produced in the early stages of the GC-T region and mediated feedback regulation during the selection process of GC. After shm and CSS, GC cells with high affinity for tumor-associated antigens eventually differentiated into mature PCs, producing IGG, IGM, and IGM, providing specific functions. So far, the mechanism of how GCS regulates the output of PBS and PCs is still unclear.

In the human melanoma cohort, Griss et al. found a subpopulation of reduced cd20 and cd19 and upregulated cd38, which was defined as a PB-like population expressing cd27, cd38 and pax5 genes. ScRNA-seq analysis showed that this subpopulation had better responses and longer overall survival with anti-pd-1 treatment. In hpv patients, hpv specific Ascs was observed in TME, suggesting an in situ and antigen-specific response. However, the relationship between Ascs and tumor cells was not simple, which largely depended on the immunoglobulins they secreted and the interaction between immunoglobulins and various tumor cell types.

Tumor-related antibodies are mainly iga and igg. Generally, in various cancers, the high expression of iga in tumors is related to the low survival rate of cancer patients such as colorectal cancer and bladder cancer. One possible explanation is that iga is related to the phenotype of Breg cells, which promote the formation of Treg cells, and Treg cells promote the conversion of Iggb cells by releasing transforming growth factor-β (TGF-β). However, latest evidence confirms that Iggb has an anti-tumor effect in ovarian cancer, and it binds to the polymeric IgA receptor (Pigr) ubiquitously expressed on the surface of ovarian cancer cells. Immunoglobulins can repair myeloid cells against extracellular oncogenic factors and make malignant tumor cells sensitive to cell killing of CD8T cells. Therefore, immunotherapy targeted at IgA and IgA secretory cells may be an effective way to treat Pigr mucosal tumors.

,Cdc,ACP and ACP promote antigen expression are closely related to antitumor B cell activity. However, recent studies have found that high IGG in TME is related to poor survival, more aggressive pathological characteristics, and low infiltration of CD8T cells. In breast cancer, primary tumor-educated B cells can gather in tumor drainage lymph nodes and secrete pathogenic IGG, targeting the glycosylated membrane protein HSPA4

Metastasis. However, this controversy may be due to different IGG subtypes. In lung adenocarcinoma, the ratios of IGG1 and IGG4 were positively correlated with non-silent mutation load, which highlighted the role of antigen presentation and direct killing of tumor cells. In addition, high IGG1 infiltration was associated with higher survival rates in patients with melanoma and patients with KRAS-mutant lung adenocarcinoma. In contrast, RNA sequencing data showed that IGG3 promotes melanoma development, which may be due to IGG3-mediated humoral reversal

It should be transient and early, with low shm rate and affinity. Another possible explanation is that monomer IGG3 has a high affinity with FCγR expressed on macrophages and natural killer cells, which is different from other subtypes. Therefore, nonspecific IGG3 binds to the vacant FCγ receptors on these cells, thus stopping their interaction with tumor-specific cytotoxic antibodies that bind on the surface of tumor cells. IGG4 also weakens IGG1-mediated anti-tumor immunity

, and promotes inflammation of melanoma. However, using tumor-specific antibodies can ensure the survival of patients more than using nonspecific autoantibodies, and promoting cytokines or chemokines produced by IGG in TME may inhibit the differentiation or cytotoxic function of T cells. Therefore, the anti-tumor or pro-tumor effect of antibodies depends not only on their biological characteristics, but also on the interaction between various cells and cytokines in TME, and pay more attention to exploring the complex network of TME from a single-cell perspective.

B and T cells

B cells and T cells act as the best partners, work together to regulate and differentiate each other, which is manifested as a large number of B cells and T cells co-infiltration into the TLS structure (Figure 3). JH     /Musc                                                                                                                                                                                                                              �
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