B Cells Are Required for Optimal CD4+ and CD8+ T Cell Tumor Immunity: Therapeutic B Cell Depletion Enhances B16 Melanoma Growth in Mice

DiLillo, David J.; Yanaba, Koichi; Tedder, Thomas F.

doi:10.4049/jimmunol.0903009

Cited by 298 publications

(229 citation statements)

References 56 publications

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“…48,49 The role of B cells in tumor progression and anti-tumor immunity is not fully elucidated. Previous studies have found that B cell depletion results in an increased tumor growth, 50 although it has also been shown, as in our case, to enhance survival in combination with checkpoint inhibitors. 51 …”

Section: Discusionsupporting

confidence: 75%

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

et al. 2018

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Ovarian cancer is frequently diagnosed as peritoneal carcinomatosis. Unlike other tumor locations, the peritoneal cavity is commonly exposed to gut-breaching and ascending genital microorganisms and has a unique immune environment. IL-33 is a local cytokine that can activate innate and adaptive immunity. We studied the effectiveness of local IL-33 delivery in the treatment of cancer that has metastasized to the peritoneal cavity. Direct peritoneal administration of IL-33 delayed the progression of metastatic peritoneal cancer. Prolongation in survival was not associated with a direct effect of IL-33 on tumor cells, but with major changes in the immune microenvironment of the tumor. IL-33 promoted a significant increase in the leukocyte compartment of the tumor immunoenvironment and an allergic cytokine profile. We observed a substantial increase in the number of activated CD4+ T-cells accompanied by peritoneal eosinophil infiltration, B-cell activation and activation of peritoneal macrophages which displayed tumoricidal capacity. Depletion of CD4+ cells, eosinophils or macrophages reduced the anti-tumor effects of IL-33 but none of these alone were sufficient to completely abrogate its positive benefit. In conclusion, local administration of IL-33 generates an allergic tumor environment resulting in a novel approach for treatment of metastatic peritoneal malignancies, such as advanced ovarian cancer.

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Section: Discusionsupporting

confidence: 75%

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

et al. 2018

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“…While these studies have been performed in B cell deficient mice, to the best of our knowledge, only few studies have analyzed a role of B cells in cancer in B cell-depleted animal models. DiLillo et al (8) demonstrated that B cell depletion induced tumor growth exacerbation when performed prior to melanoma implantation; no effect was evidenced when depletion was performed following tumor implantation. These results led the authors to postulate that B cells were required for the onset of T cell activation in the melanoma model, though a promoting action of B cells on tumor growth was not observed (8).…”

Section: Discussionmentioning

confidence: 99%

“…DiLillo et al (8) demonstrated that B cell depletion induced tumor growth exacerbation when performed prior to melanoma implantation; no effect was evidenced when depletion was performed following tumor implantation. These results led the authors to postulate that B cells were required for the onset of T cell activation in the melanoma model, though a promoting action of B cells on tumor growth was not observed (8). In another system Kim et al (15) found that B cell depletion following the establishment of the tumor not only retarded tumor growth but augmented the immunotherapeutic efficacy of a vaccine approach.…”

Section: Discussionmentioning

confidence: 99%

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B cells inhibit the antitumor immunity against an established murine fibrosarcoma

et al. 2017

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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

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“…Enhanced antitumor T-cell responses in B-cell-deficient mice suggest that B lymphocytes can hamper T-cell immunity [1,2]. In contrast, a recent study by DiLillo et al [3] demonstrated that T-cell proliferation as well as Th1 responses was hampered after B-cell depletion, indicating a crucial role for B lymphocytes in the initiation of a T-cell response. However, none of these studies addressed the role of circulating antibodies in the induction of T-cell immunity by DCs.…”

Section: Introductionmentioning

confidence: 99%

Circulating specific antibodies enhance systemic cross‐priming by delivery of complexed antigen to dendritic cells in vivo

et al. 2012

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B Cells Are Required for Optimal CD4+ and CD8+ T Cell Tumor Immunity: Therapeutic B Cell Depletion Enhances B16 Melanoma Growth in Mice

Cited by 298 publications

References 56 publications

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

B cells inhibit the antitumor immunity against an established murine fibrosarcoma

Circulating specific antibodies enhance systemic cross‐priming by delivery of complexed antigen to dendritic cells in vivo

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