B cells inhibit the antitumor immunity against an established murine fibrosarcoma

Abstract

Abstract. Despite the classic role of B cells in favoring the immune response, an inhibitory action of B lymphocytes in tumor immunity has emerged in certain studies. In methylcolanthrene-induced murine fibrosarcoma (MCC), the loss of immunogenicity and the establishment of tolerance are paralleled by systemic immune suppression and the appearance of B + IL-10 + cells in tumor-draining lymph nodes. The present study aimed to assess the role of the B + IL-10 + cell population in the immune evasion and tolerance induced by MCC through the depletion of B cells in mice at various times of tumor progression: Prior to or subsequent to tumor implantation. Tumor growth and immunological parameters were evaluated. B cell depletion prior to tumor inoculum enhanced tumor growth, initiating the onset of the tumor-induced systemic immune response; however, an increase in the T regulatory cells (Tregs) at the tumor-draining lymph node could account for tumor exacerbation. B cell depletion once the tumor was established resulted in decreased tumor growth and a delayed onset of tolerance. Additionally, B cell absence exacerbated T cell dependent-tumor rejection, reduced Tregs and increased cytotoxic CD8 + T cells. In vitro analysis showed a direct effect of B cells upon T cell proliferation.In conclusion, B cell depletion exerts opposite effects when performed prior to or subsequent to tumor implantation. In this initially immunogenic tumor, B cell absence would delay the establishment of immunological tolerance probably by unmasking a pre-existing antitumor response. The present findings elucidate the convenience of modulating B cells in the development of future and more effective immunotherapies against cancer. IntroductionThe role of the host immune system in the control of cancer progression has been assessed for several years; at present, it is vastly accepted that antitumor immunity occurs and that numerous tumors have developed mechanisms to escape immune control, leading to malignant progression (1). The mechanisms responsible for antitumor immunity failure in individuals with cancer include a wide diversity of soluble immunosuppressive factors, including transforming growth factor β (TGFβ), interleukin 10 (IL-10), reactive oxygen species (ROS), enzymes and inhibitory ligands such as Fas ligand (FasL) or TNF-related apoptosis-inducing ligand, released by tumor cells or by other regulatory cells in the tumor microenvironment (2). The majority of immunotherapies against cancer aim to counteract the action of regulatory cells in order to achieve tumor remission or prevent recurrences; of these, T regulatory cells (Tregs) have been the major focus of efforts to therapeutically modulate their inhibitory activity (3,4

Tumor-draining lymph nodes: At the crossroads of metastasis and immunity

“…B cells rapidly expand in response to tumor challenge and up-regulate immunoglobulin-related genes in TDLNs relative to NDLNs (19,105,106); however, the effects of antibodies on tumor progression seem to vary widely based on tumor model, anatomical location, and timing. Tumor-binding immunoglobulin G (IgG) antibodies can accumulate in tumors where they are taken up by DCs to initiate cytotoxic T cell-mediated tumor clearance (107), and B cell depletion before tumor inoculation actually accelerates primary tumor growth (108). However, when B cells are depleted in established tumor-bearing mice, IFN-producing CD8 + T cells accumulate in TDLNs and lead to improved tumor control (108).…”

“…Tumor-binding immunoglobulin G (IgG) antibodies can accumulate in tumors where they are taken up by DCs to initiate cytotoxic T cell-mediated tumor clearance (107), and B cell depletion before tumor inoculation actually accelerates primary tumor growth (108). However, when B cells are depleted in established tumor-bearing mice, IFN-producing CD8 + T cells accumulate in TDLNs and lead to improved tumor control (108). These findings suggest that B cells may be protective but undergo a tumor-dependent shift in function that can support tumor progression in TDLNs.…”

Phenotypic Peculiarities of Dendritiс Cells Differentiated From Blood Monocytes in Patients With Kidney Cancer

“…Во-первых, это формирование, активация и перераспределение (миграция) в организме всех клеток иммунной системы, участвующих в инициации и развитии противоопухолевого иммунитета [5,7,28]. И, во-вторых, развитие «защитной» реакции со стороны опухоли, реализующейся в изменении антигенной структуры малигнизированных клеток, синтезом различных цитокинов и других биологически активных веществ, что приводит к ингибированию противоопухолевого иммунитета на различных этапах развития иммунной реакции [1,20,33 [3,11,27]. Однако в ряде работ отмечается, что генерация ДК из моноцитов периферической крови осуществляется недостаточно эффективно: формируются ДК со сниженными функциональными свойствами.…”

“…Функциональная активность ДК, дифференцированных из моноцитов периферической крови, может во многом зависеть от функционального состояния самих моноцитов и от эффекторных и регуляторных процессов в иммунной системе, которые формируются в процессе развития иммуноопосредованных заболеваний. Доказано, что развитие опухоли в организме обусловливает ингибирование противоопухолевого иммунитета, которое реализуется через нарушение соотношения эффекторных и регуляторных субпопуляций Т-лимфоцитов, синтеза супрессирующих цитокинов и снижение активности эффекторных реакций [1,20,32]. Ранее нами установлено, что у больных раком почки (РП) в периферической крови повышается количество CD14 low CD16 + моноцитов, выявляется дисбаланс в экспрессии активационных маркеров и снижается интенсивность респираторного взрыва [4].…”

Tumor-Draining Lymph Node Reconstruction Promotes B Cell Activation During E0771 Mouse Breast Cancer Growth

“…B cell-deficient mice inhibit tumor growth through increased cytotoxic CD8 T cell and reduced regulatory T cell populations in several tumor models, such as EL4 thymoma, MC38 colon carcinoma, and EMT-6 breast carcinoma ( Shah et al, 2005 ; Tadmor et al, 2011 ; Zhang et al, 2013 ). In a fibrosarcoma model, depleting B cells before tumor implantation accelerates tumor growth while depleting B cells after tumor establishment suppresses tumor growth, suggesting that B cells may contribute to pro-tumor or anti-tumor immunity depending on the stage of tumor growth ( Maglioco et al, 2017 ).…”