B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

Abstract

The immune system plays a crucial role in cancer development either by fostering tumor growth or destroying tumor cells, which has open new avenues for cancer immunotherapy. It was only over the last decade that the role of B cells in controlling anti-tumor immune responses in the tumor milieu has begun to be appreciated. B and plasma cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade, even though their effector functions extend beyond the classical humoral immunity. In tumor tissues, B cells can be found in lymphoid aggregates, known as tertiary lymphoid structures (TLSs), well-organized non-encapsulated structures composed of immune and stromal cells. These structures reflect a process of lymphoid neogenesis occurring in peripheral tissues upon long-lasting exposure to inflammatory signals. The TLS provides an area of intense B cell antigen presentation that can lead to optimal T cell activation and effector functions, as well as the generation of effector B cells, which can be further differentiated in either antibody-secreting plasma cells or memory B cells. Of clinical interest, the crosstalk between B cells and antigen-experienced and exhausted CD8+ T cells within mature TLS was recently associated with improved response to immune checkpoint blockade (ICB) in melanoma, sarcoma and lung cancer. Otherwise, B cells sparsely distributed in the tumor microenvironment or organized in immature TLSs were found to exert immune-regulatory functions, inhibiting anti-tumor immunity through the secretion of anti-inflammatory cytokines. Such phenotype might arise when B cells interact with malignant cells rather than T and dendritic cells. Differences in the spatial distribution likely underlie discrepancies between the role of B cells inferred from human samples or mouse models. Many fast-growing orthotopic tumors develop a malignant cell-rich bulk with reduced stroma and are devoid of TLSs, which highlights the importance of carefully selecting pre-clinical models. In summary, strategies that promote TLS formation in close proximity to tumor cells are likely to favor immunotherapy responses. Here, the cellular and molecular programs coordinating B cell development, activation and organization within TLSs will be reviewed, focusing on their translational relevance to cancer immunotherapy.

Colorectal Cancer-Associated Immune Exhaustion Involves T and B Lymphocytes and Conventional NK Cells and Correlates With a Shorter Overall Survival

“…TRAF1 belongs to the Tumor necrosis factor receptor (TNFR)-associated factors (TRAF) protein family, which plays important roles in the immune system as key intracellular signaling molecules in TNFR, Toll-like receptor (TLR), cytokine and antigen receptor signaling pathways ( 19 ). TRAF1 expression in T and B lymphocytes can be induced by different stimuli that activate the transcription factor NF-κB ( 49 – 51 ), and may act as both positive and negative regulator of immune signaling.…”

“…the progressive loss of effector function due to chronic low-affinity antigen stimulation, is essential in maintaining immune homeostasis by regulating the duration and the magnitude of T cell responses, through a reduced proliferation, impaired effector functions, and elevated and sustained expression of multiple inhibitory receptors, known as immune checkpoint proteins (41). It is becoming progressively clear that the range of checkpoint inhibitors extends well beyond the few targets of current immunotherapy (41), and that functional exhaustion is not an exclusive matter of T lymphocytes, but heavily involves other immune cell populations (12,(42)(43)(44), that take part in mounting an effective immune response (19,45,46).…”

“…Immunostained sections were examined by two pathologists in a blind fashion, with very good agreement (κ value = 0.89). Representative images of immunostained sections for exhaustion markers were captured in the stroma, between tumor glands, or in lymphoid aggregates, because in these areas their expression was more evident, regardless of the number of lymphoid-like structures in tumor samples from short versus long-term survivors, which has been the subject of previous investigations ( 18 , 19 ).…”

Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma

“…The association between SLRs and immunotherapy outcomes in lung cancer seems not clear. On the other hand, although total TLS and germinal center-positive (GC+) TLS subset scores were demonstrated to predict survival in resected NSCLC patients ( 29 ), most studies suggested that only TLSs with GC were functional, and B cells in immature TLSs could adopt a regulatory phenotype and inhibit immune reactions ( 30 ). Moreover, we noted the predominant inhibitory Treg cells in post treatment tumor and PD-L1 expression in the lymph node for their crucial roles in immunosuppression.…”

Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment

“…Also, in some cases, notably for HCC and GC, viral infections were associated with high levels of regulatory T cells ( Table 1 ). Notwithstanding, some cancers associated with viruses, such as HPV-associated HNSCC, have increased lymphoid aggregates composed of B and T cells known as tertiary lymphoid structures ( 127 , 129 ), which may serve as niches for antigen presentation in the TME and are associated with improved prognosis and response to ICB in multiple cancers ( 145 ).…”