B Cell Function in the Tumor Microenvironment.

The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.

TGF-ß-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.

Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer.

The composition of the intestinal microbiota is associated with both the development of tumors and the efficacy of anti-tumor immunity. Here, we examined the impact of microbiota-specific T cells in anti-colorectal cancer (CRC) immunity. Introduction of Helicobacter hepaticus (Hhep) in a mouse model of CRC did not alter the microbial landscape but increased tumor infiltration by cytotoxic lymphocytes and inhibited tumor growth. Anti-tumor immunity was independent of CD8+ T cells but dependent upon CD4+ T cells, B cells, and natural killer (NK) cells. Hhep colonization induced Hhep-specific T follicular helper (Tfh) cells, increased the number of colon Tfh cells, and supported the maturation of Hhep+ tumor-adjacent tertiary lymphoid structures. Tfh cells were necessary for Hhep-mediated tumor control and immune infiltration, and adoptive transfer of Hhep-specific CD4+ T cells to Tfh cell-deficient Bcl6fl/flCd4Cre mice restored anti-tumor immunity. Thus, introduction of immunogenic intestinal bacteria can promote Tfh-associated anti-tumor immunity in the colon, suggesting therapeutic approaches for the treatment of CRC.

Harnessing the power of oncolytic virotherapy and tertiary lymphoid structures to amplify antitumor immune responses in cancer patients.

Tertiary lymphoid structures (TLS) are ectopic aggregates of immune cells that develop in non-lymphoid tissues under persistent inflammation. Since their presence has been associated with a better prognosis in cancer patients, modulating TLS formation is being part of new challenges in immunotherapy. Although mechanisms underlying TLS genesis are still not fully understood, different strategies have been developed in preclinical models to induce their formation and ultimately enhance antitumor responses. Herein, we will discuss a new approach that would consist in using oncolytic viruses (OV). These viruses have the unique feature to preferentially infect, replicate in and kill cancer cells. Their immunoadjuvant property, their use as a vector of therapeutic molecules and their selectivity for cancer cells, make them an attractive strategy to induce TLS in the tumor microenvironment. This review will examine the current knowledge about TLS neogenesis, approaches for inducing them, and relevance of using OV for this purpose, especially in combination with immunotherapy such as immune checkpoint blockade.

Neglected no more: B cell-mediated anti-tumor immunity.

Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors.

Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13+CD103+CD8+ Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.

BACKGROUND & AIMS: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy. METHODS: Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13)+ cluster of differentiation (CD)103+CD8+ Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13+CD103+CD8+ Trm cells was determined in vitro and in vivo. The effect of CXCL13+CD103+CD8+ Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy. RESULTS: The presence of TLS and CXCL13+CD103+CD8+ Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103+CD8+ Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103+CD8+ Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103+CD8+ Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13+CD103+CD8+ Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner. CONCLUSIONS: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13+CD103+CD8+ Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13+CD103+CD8+ Trm cells for advancing immunotherapy strategies in GC.

Peripheral helper T cells, mavericks of peripheral immune responses.

Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.

Combination of tumor antigen drainage and immune activation to promote a cancer-immunity cycle against glioblastoma.

While conventional cancer modalities, such as chemotherapy and radiotherapy, act through direct killing of tumor cells, cancer immunotherapy elicits potent anti-tumor immune responses thereby eliminating tumors. Nevertheless, promising outcomes have not been reported in patients with glioblastoma (GBM) likely due to the immune privileged status of the central nervous system and immunosuppressive micro-environment within GBM. In the past years, several exciting findings, such as the re-discovery of meningeal lymphatic vessels (MLVs), three-dimensional anatomical reconstruction of MLV networks, and the demonstration of the promotion of GBM immunosurveillance by lymphatic drainage enhancement, have revealed an intricate communication between the nervous and immune systems, and brought hope for the development of new GBM treatment. Based on conceptual framework of the updated cancer-immunity (CI) cycle, here we focus on GBM antigen drainage and immune activation, the early events in driving the CI cycle. We also discuss the implications of these findings for developing new therapeutic approaches in tackling fatal GBM in the future.

Spatial tertiary lymphoid structures imply response to anti-PD-1 plus anlotinib in advanced non-small cell lung cancer.

Despite breakthroughs of immunotherapy synergistically combined with blockade of vascular endothelial growth factor receptor, several patients with advanced non-small cell lung cancer (NSCLC) experience non-response or followed relapse. Organized lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are found to be associated with improved response to immunotherapy. Here, we explore the landscapes of TLSs in tumour tissues from a real-world retrospective study. Our investigation showed that with a median follow-up of 11.2 months, the ORR was 28.6% (18/63, 95% CI 17.9-41.3) and the median PFS was 6.1 (95% CI 5.5-6.6) months in NSCLC patients treated with PD-1 blockade combined with anlotinib. By multiplex immunofluorescence (mIF) analysis, spatially, more TLSs and high CD20+ B-cell ratio in TLSs were associated with higher ORR. High density of intratumoral CD8+ T cells showed better ORR and PFS. The numbers of CD8+ T cells with a distance within 20 µm and 20-50 µm between tumour cells were higher in responders than non-responders. But responders had significantly higher TLSs within 20 µm rather than within 20-50 µm of tumour cells than non-responders. The inflamed immunophenotyping occupied higher proportions in responders and was associated with better PFS. Besides, tumour cells in non-responders were found more temporal cell-in-cell structures than responders, which could protect inner cells from T-cell attacks. Taken together, landscape of TLSs and proximity architecture may imply superior responses to PD-1 blockade combined with anlotinib for patients with advanced non-small cell lung cancer.

Prognostic Effect of Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated Gastric Carcinomas Measured by Digital Image Analysis.

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent tumor-infiltrating lymphocytes (TILs) and has a favorable prognosis. Tertiary lymphoid structures (TLS), characterized by ectopic aggregated lymphocytes with high-endothelial venules (HEV), are associated with favorable outcomes in various solid tumors. We hypothesized that EBVaGC, characterized by intense TILs, may be closely associated with TLS or HEV. To test this hypothesis, we digitally analyzed the TLS, HEV, and TILs in 73 surgically resected advanced EBVaGCs. For HEV, dual MECA-79 and CD31 dual immunohistochemistry were performed, and the ectopic expression of MECA-79 in tumor cells was measured. In 73 patients with EBVaGC, a high-TLS ratio was found in 29 (39.7%) cases, high-tumor-associated HEV density in 44 (60.3%) cases, and high-CD8+ TIL density in 38 (52.1%) cases. Ectopic tumor expression of MECA-79 was observed in 36 patients (49.3%) cases. A low-TLS ratio and tumor-associated HEV density were significantly associated with lymph node metastasis (P = .005 and .042, respectively). Ectopic MECA-79 expression was significantly associated with lymph node metastasis (P = .003). Patients with a low-TLS ratio (P = .038), low-HEV density (P = .042), and ectopic tumor MECA-79 expression (P = .032) had significantly worse prognoses. In conclusion, TLS ratio and HEV density affect the survival of patients with EBVaGC and may be related to the immune response that interrupts lymph node metastasis.

Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Analyses of tertiary lymphoid structures observed in cases of Merkel cell carcinoma showing spontaneous regression.

Merkel cell carcinoma (MCC) is a high-grade skin cancer, but spontaneous regression is observed at a markedly higher frequency than in other carcinomas. Although spontaneous regression is a phenomenon that greatly impacts treatment planning, we still cannot predict it. We previously reported on the prognostic impact of the presence or absence of tertiary lymphoid structures (TLS) and of Merkel cell polyomavirus (MCPyV) infection. To learn more about the spontaneous regression of MCC, detailed analyses were performed focusing on spontaneous regression cases. We collected 71 Japanese patients with MCC including 6 cases of spontaneous regression. Samples were analysed by immunostaining, spatial single-cell analysis using PhenoCycler, and RNA sequencing using the next-generation sequencer (NGS). All 6 cases of spontaneous regression were positive for MCPyV. TLS was positive in all 5 cases analysed. Spatial single-cell analyses revealed that PD-L1-positive tumour cells were in close proximity to CD20-positive B cell and CD3-, 4-positive T cells. Gene set enrichment analysis between MCPyV-positive and TLS-positive samples and other samples showed significantly high enrichment of "B-cell-mediated immunity" gene sets in the MCPyV-positive and TLS-positive groups. In conclusion, TLS may play an important role in the spontaneous regression of MCC.

Constructing a prognostic model for colon cancer: insights from immunity-related genes.

BACKGROUND: Colon cancer (CC) is a malignancy associated with significant morbidity and mortality within the gastrointestinal tract. Recurrence and metastasis are the main factors affecting the prognosis of CC patients undergoing radical surgery; consequently, we attempted to determine the impact of immunity-related genes. RESULT: We constructed a CC risk model based on ZG16, MPC1, RBM47, SMOX, CPM and DNASE1L3. Consistently, we found that a significant association was found between the expression of most characteristic genes and tumor mutation burden (TMB), microsatellite instability (MSI) and neoantigen (NEO). Additionally, a notable decrease in RBM47 expression was observed in CC tissues compared with that in normal tissues. Moreover, RBM47 expression was correlated with clinicopathological characteristics and improved disease-free survival (DFS) and overall survival (OS) among patients with CC. Lastly, immunohistochemistry and co-immunofluorescence staining revealed a clear positive correlation between RBM47 and CXCL13 in mature tertiary lymphoid structures (TLS) region. CONCLUSION: We conclude that RBM47 was identified as a prognostic-related gene, which was of great significance to the prognosis evaluation of patients with CC and was correlated with CXCL13 in the TLS region.

Correlation of Neuroendocrine Differentiation with a Distinctively Suppressive Immune Microenvironment in Gastric Cancer.

INTRODUCTION: Neuroendocrine neoplasms (NENs) harbored significantly suppressive tumor immune microenvironments (TIMEs). However, the immunological effects of neuroendocrine differentiation (NED) on non-NENs, such as gastric cancer (GC), were unknown. METHODS: Between pure gastric cancer (PGC) and GC-NED, TIME features were scored based on expression data and validated on serial whole-tissue sections of surgical samples, with tertiary lymphoid structures (TLSs) and the extra-TLS zone evaluated independently using multi-marker immunohistochemical staining. Risk analyses of TIME features on tumor behaviors were performed in GC-NED. The universal immunological effects of NED were explored preliminarily in adenocarcinomas arising in other organs. RESULTS: Based on over 11,500 annotated TLSs and 2,700 extra-TLS zones, compared with PGC, GC-NED harbored a distinctively more suppressive TIME characterized by increased but immature TLSs, with higher naïve B-cell and follicular regulatory T-cell densities and downregulated TLS maturation-related cell ratios inside TLSs; increased naïve B-cell and regulatory T-cell densities; and a high proportion of exhausted T cells in the extra-TLS zone. The upregulated tumor PD-L1 expression and its close correlations with TLS formation and maturation were remarkable exclusively in GC-NED. TIME features, especially those regarding TLSs, were significantly correlated with tumor growth and invasion. The desynchrony between TLS formation and maturation and increased naïve or regulatory immune cell infiltration was observed in adenocarcinomas of the colorectum, pancreas, lung, and prostate. CONCLUSION: NED highlighted a distinct GC entity with more suppressive TIME features correlated with tumor behaviors, indicating a cohort that would benefit more from immunotherapies.

Prognostic significance of tertiary lymphoid structures in gastric neuroendocrine carcinoma with association to delta-like ligand 3 and neuroendocrine expressions.

BACKGROUND: Gastric neuroendocrine carcinomas (NECs) are rare cancers with highly aggressive behavior. Although tertiary lymphoid structures (TLSs) are well-known prognostic factors in various cancers, their role in gastric NECs remain unexplored. Unique immunohistochemical subtypes of pulmonary NECs have been discovered, however, their feasibility in gastric NECs is unknown. METHODS: The presence and maturation of TLSs (lymphoid aggregates, primary and secondary follicles) were assessed in 48 surgically resected gastric NECs and were compared with immunohistochemical subtypes, using a panel of ASCL1, NeuroD1, POU2F3, YAP1, and DLL3 with three neuroendocrine (NE) markers. RESULTS: Patients with secondary follicles had significantly better overall survival (OS) and recurrence-free survival (RFS; both, p = 0.004) than those without them. Based on the hierarchical clustering, gastric NECs were classified into all low/negative (31%), high-YAP1 (19%), high-DLL3/low-NE (29%), and high-NE (21%) expression groups. The high-DLL3/low-NE group was associated with absent TLSs (p = 0.026) and showed the worst OS (p = 0.026). Distant metastasis and a lack of secondary follicles were poor independent prognostic factors of OS and RFS. CONCLUSION: The assessment of TLSs is a feasible and potent biomarker for gastric NECs, thus enabling better prognosis and more effective immunotherapy. Furthermore, gastric NECs can be categorized as four immunohistochemically distinct groups, of which the high-DLL3/low-NE group has the worst OS with lack of TLSs.

Tertiary lymphoid structures in tongue cancer: Association with clinicopathological parameters, preoperative S-1 chemotherapy response, and prognosis.

BACKGROUND: Tertiary lymphoid structures (TLSs) are observed in cancer-invasive sites of various organs, and show evidence of tumor-specific B and/or T cells, suggesting an active humoral antitumor response. The aim of this study was to evaluate the relationship between TLSs and prognosis in patients with tongue squamous cell carcinoma (TSCC) after preoperative S-1 chemotherapy. METHODS: Among 196 TSCC cases, 111 patients who received preoperative S-1 chemotherapy were compared to 85 patients who did not receive chemotherapy. We investigated the incidence of TLSs in both preoperative biopsy and resected specimens. RESULTS: TLSs were present in 24 (12%) biopsy specimens and 31 (16%) resected specimens. TLSs were associated with clinicopathologically advanced cases and positivity for lymphatic invasion. None of the cases with pStage 0 (i.e., noninvasive cancer) showed TLSs. In preoperative S-1 chemotherapy cases, TLSs were significantly more common in those treated with S-1 for more than 21 days and in those with treatment effects 0, Ia, and Ib. TLSs may not be a favorable prognostic factor by themselves but maybe a prognostic factor when combined with preoperative S-1 treatment. CONCLUSION: The presence of TLSs was suggested to be a factor indicating a favorable prognosis when considering the indication for preoperative S-1 chemotherapy. The synergistic effect of S-1 by activating antitumor immunity may be associated with a better prognosis in TSCC patients with TLSs.

Tertiary Lymphoid Structures Gene Signature Predicts Prognosis and Immune Infiltration Analysis in Head and Neck Squamous Cell Carcinoma.

Objectives: This study aims to assess the prognostic implications of gene signature of the tertiary lymphoid structures (TLSs) in head and neck squamous cell carcinoma (HNSCC) and scrutinize the influence of TLS on immune infiltration. Methods: Patients with HNSCC from the Cancer Genome Atlas were categorized into high/low TLS signature groups based on the predetermined TLS signature threshold. The association of the TLS signature with the immune microenvironment, driver gene mutation status, and tumor mutational load was systematically analyzed. Validation was conducted using independent datasets (GSE41613 and GSE102349). Results: Patients with a high TLS signature score exhibited better prognosis compared to those with a low TLS signature score. The group with a high TLS signature score had significantly higher immune cell subpopulations compared to the group with a low TLS signature score. Moreover, the major immune cell subpopulations and immune circulation characteristics in the tumor immune microenvironment were positively correlated with the TLS signature. Mutational differences in driver genes were observed between the TLS signature high/low groups, primarily in the cell cycle and NRF2 signaling pathways. Patients with TP53 mutations and high TLS signature scores demonstrated a better prognosis compared to those with TP53 wild-type. In the independent cohort, the relationship between TLS signatures and patient prognosis and immune infiltration was also confirmed. Additionally, immune-related biological processes and signaling pathways were activated with elevated TLS signature. Conclusion: High TLS signature is a promising independent prognostic factor for HNSCC patients. Immunological analysis indicated a correlation between TLS and immune cell infiltration in HNSCC. These findings provide a theoretical basis for future applications of TLS signature in HNSCC prognosis and immunotherapy.

A model of tertiary lymphatic structure-related prognosis for penile squamous cell carcinoma.

BACKGROUND: We investigated the feasibility of the tertiary lymphoid structure (TLS) as a prognostic marker for penile squamous cell carcinoma(SCC). METHODS: We retrospectively collected data from 83 patients with penile squamous cell carcinoma. H&E-stained slides were reviewed for TLS density. In addition, clinical parameters were analyzed, the prognostic value of these parameters on overall survival (OS) was evaluated using ‒ Kaplan-Meier survival curves, and the prognostic value of influencing factors was evaluated using Cox multifactor design nomogram analysis. RESULT: BMI, T, N, and M are significant in the survival curve with or without tertiary lymphoid structure. BMI, T, N, M and TLS were used to construct a prognostic model for penile squamous cell carcinoma, and the prediction accuracy reached a consensus of 0.884(0.835-0.932), and the decision consensus reached 0.581(0.508-0.655). CONCLUSION: TLS may be a positive prognostic factor for penile squamous cell carcinoma, and the combination of BMI, T, N and M can better evaluate the prognosis of patients.

Characteristics and clinical significance of tertiary lymphoid structures in OSCC.

OBJECTIVES: This study aimed to investigate the characteristics of tertiary lymphoid structures (TLSs) in oral squamous cell carcinoma (OSCC) and their association with clinical and pathological features. MATERIALS AND METHODS: 12 TLS-related chemokines in TCGA database were analyzed to investigate the TLSs in OSCC. The density, maturity, and location of TLSs in a large cohort of 189 OSCC patients (114 of which had clinical and prognostic information) were assessed. And the significance between TLSs and clinicopathologic characteristics was analyzed. RESULTS: Bioinformatics and analysis showed that TLSs were associated with better clinical outcomes in OSCC. Histological staining and analysis showed that the overall survival rate of the high-density group (71/112, 63.4%) was significantly higher (p < 0.0001) than that of the low-density group (41/112, 36.6%), and the high-density group had fewer lymph node metastases (50.0%/68.3%, p = 0.021). And TLSs were divided into 4 types according to the maturity and location. Different types of TLSs are associated with prognosis (OS, p < 0.0001), clinical features (T stage, p = 0.028; degree of differentiation, p = 0.043), and precancerous lesion types (OSF, p = 0.049) of OSCC patients. CONCLUSION: TLSs were closely associated with better OSCC prognosis, and a more systematic classification may better guide the formulation of further treatment options.

Humoral immune responses: Unsung heroes of the war on cancer.

Solid cancers progress from primordial lesions through complex interactions between tumor-promoting and anti-tumor immune cell types, ultimately leading to the orchestration of humoral and T cell adaptive immune responses, albeit in an immunosuppressive environment. B cells infiltrating most established tumors have been associated with a dual role: Some studies have associated antibodies produced by tumor-associated B cells with the promotion of regulatory activities on myeloid cells, and also with direct immunosuppression through the production of IL-10, IL-35 or TGF-ß. In contrast, recent studies in multiple human malignancies identify B cell responses with delayed malignant progression and coordinated T cell protective responses. This includes the elusive role of Tertiary Lymphoid Structures identified in many human tumors, where the function of B cells remains unknown. Here, we discuss emerging data on the dual role of B cell responses in the pathophysiology of human cancer, providing a perspective on future directions and possible novel interventions to restore the coordinated action of both branches of the adaptive immune response, with the goal of maximizing immunotherapeutic effectiveness.