CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade

Sato, Yuji; Bolzenius, Jennifer K.; Eteleeb, Abdallah M.; Su, Xinming; Maher, Christopher A.; Sehn, Jennifer K.; Arora, Vivek

doi:10.1172/jci.insight.121062

Cited by 36 publications

(51 citation statements)

References 47 publications

(62 reference statements)

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“…The significance of Th1 cells to the anti-tumor response is highlighted by a recent study investigating the effect of checkpoint blockade in a murine bladder cancer model. Analysis of the immune infiltrates from tumor and lymph nodes post treatment revealed an expansion of IFN-γ producing CD4 T cells (Th1) and the neutralization of IFN-γ abolished the anti-tumor effect of checkpoint blockade suggesting the key role for these cells and this cytokine (86). Additionally, a Th1 biased response is known to be essential to successful BCG therapy (87, 88) with a recent study demonstrating a transient but significant recruitment of CD4 helper T cells to the bladder in a murine model- recruitment which far outstripped that of cytotoxic CD8 or regulatory FoxP3 T cells (89).…”

Section: Cd4 Helper T Cells and The Th1/th2 Axismentioning

confidence: 99%

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Joseph

Enting

2019

Front. Oncol.

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Immunosurveillance, which describes the immunologically mediated elimination of transformed cells, has been widely accepted in the context of bladder cancer for many decades with the successful use of Bacillus-Calmette Guerin for superficial bladder cancer since the 1970s. With the emergence of checkpoint inhibitor blockade in the treatment of urothelial cancers, there has been a resurgent interest in the immunology of bladder cancer. The theory of cancer immunoediting proposes that the immune system has both pro-tumorigenic and anti-tumor effects, the balance between the two determining the progression of an individual tumor. However, whilst there is evidence for the action of various immune cell populations in bladder cancer, a cohesive picture of the immune response to bladder cancer and its driving forces are still lacking. Additionally, little is still known about the normal immune landscape of the bladder. Future progress in bladder cancer therapeutic approaches will require a strong foundation in understanding the immunology of this disease. This review considers the evidence for the role of the main immune cell populations, both innate and adaptive, in the immune response to bladder cancer. Recent research and overarching themes in the immune response to bladder cancer are explored. The minimal evidence regarding the normal immune landscape of the human bladder is also summarized to contextualize downstream immune responses. Of specific interest are the innate and myeloid populations, some of which are resident in the human bladder and which have significant effects on downstream adaptive tumor immunity. We discuss factors which restrain the efficacy of populations known to have anti-tumor activity such as cytotoxic T cells, including the constraints on checkpoint blockade. Additionally, the effects on the immune response of tumor intrinsic factors such as the genomic subtype of bladder cancer and the effect of common therapies such as chemotherapy and intravesical Bacillus Calmette-Guerin are considered. A significant theme is the polarization of immune responses within the tumor by a heavily immunosuppressive tumor microenvironment which affects the phenotype of multiple innate and adaptive populations. Throughout, clinical implications are discussed with suggestions for future research directions and therapeutic targeting.

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Section: Cd4 Helper T Cells and The Th1/th2 Axismentioning

confidence: 99%

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Joseph

Enting

2019

Front. Oncol.

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“…In addition to aiding in the productive priming of CD8 + T cells in secondary lymphoid organs, effector roles of CD4 + T cells in the tumor microenvironment have been proposed. These include the activation of local NK cells via secretion of effector cytokines, recruitment of CD8 + T cells by IFNγ‐inducible chemokines such as CXCL‐10, and even class‐II dependent killing of tumor cells 78–80 . In a recent publication from the Schreiber laboratory, KPC ( LSL‐Kras G12D/+ ; LSL‐Trp53 R172H/+ ; Pdx‐1‐Cre ) tumors lacking natural NeoAg were transduced to express a single MHC‐I‐restricted NeoAg with or without an additional MHC‐II‐restricted NeoAg 81 .…”

Section: Help In Therapeutic Contextmentioning

confidence: 99%

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Brightman

Naradikian

Miller

et al. 2020

Journal of Leukocyte Biology

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The goal of precision immunotherapy is to direct a patient's T cell response against the immunogenic mutations expressed on their tumors. Most immunotherapy approaches to‐date have focused on MHC class I‐restricted peptide epitopes by which cytotoxic CD8+ T lymphocytes (CTL) can directly recognize tumor cells. This strategy largely overlooks the critical role of MHC class II‐restricted CD4+ T cells as both positive regulators of CTL and other effector cell types, and as direct effectors of antitumor immunity. In this review, we will discuss the role of neoantigen specific CD4+ T cells in cancer immunotherapy and how existing treatment modalities may be leveraged to engage this important T cell subset.

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“…For example, the proportions of activated CD4 + T memory cells, resting dendritic cells and CD8 + T cells were the highest in Immunity_High. The basic function of ICIs was to exert antitumor effects by enhancing the function of CD8 + T cells, while CD4 + T cells and dendritic cells could also play a supporting role in this process (16,17). Previous studies on bladder cancer, prostate cancer, renal cancer, and colorectal cancer had reported that the level of CD8 + T cell infiltration was positively correlated with tumor prognosis and responsiveness to immunotherapy (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies on BC have reported that enrichment in immune cells infiltration of BC tissue was a strong indicator for immunotherapy response ( 14 , 15 ). Furtherly, the relative proportions of different types of T cells, macrophages, and other tumor-infiltration lymphocytes (TILs) are closely related to the immune characteristics and prognosis of BC and other tumors ( 16 , 17 ). Besides, the significant correlation between the expressions of the PD-L1 and human leukocyte antigen (HLA) genes and the immunotherapy response has also been demonstrated by previous studies ( 8 , 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Classification of Muscle-Invasive Bladder Cancer Based on Immunogenomic Profiling

et al. 2020

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There is a significant heterogeneity in the immunotherapeutic responsiveness of each muscle-invasive bladder cancer (MIBC) patient. In our research, we aimed to identify a novel classification of MIBC based on immunogenomic profiling that may facilitate the reasonable stratification of prognosis and response to immunotherapy. The single-sample gene-set enrichment analysis (ssGSEA) was used to analyze the RNA-seq data of 29 important immune signatures from TCGA. Unsupervised hierarchical clustering was performed to identify an immunogenomic classification of MIBC. Then, we assessed the features of the classification in prognosis, immune infiltration, tumor-infiltration lymphocytes, HLA genes, and PD-L1 expression level. A total of 399 MIBC samples were included and three subtypes named Immunity_High, Immunity_Medium, and Immunity_Low were identified. The Immunity_High had a significant advantage in overall survival over the Immunity_Medium and Immunity_Low (p = 0.046 and p = 0.024). From Immunity_Low to Immunity_High, immune cell infiltration and stromal content showed an upward trend (p < 0.001). Meanwhile, Immunity_High was associated with a significantly higher proportion of TILs including dendritic cells resting, macrophages M1, mast cells resting, T cells CD4 memory activated, and T cells CD8 +. And the expression levels of all HLA genes and PD-L1 of Immunity_High were the highest, consistent (p < 0.001). Two hundred ninety eight MIBC patients treated with immunotherapy from the IMvigor210 were included to form an independent validation cohort to verify the robustness of immunogenomic classification and the ability to predict the response to immunotherapy. This classification had potential clinical implications for predicting prognosis and immunotherapeutic responsiveness of MIBC patients.

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CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade

Cited by 36 publications

References 47 publications

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Classification of Muscle-Invasive Bladder Cancer Based on Immunogenomic Profiling

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