Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

Mantuano, Natália Rodrigues; Natoli, Marina; Zippelius, Alfred; Läubli, Heinz

doi:10.1136/jitc-2020-001222

Cited by 76 publications

(49 citation statements)

References 178 publications

(211 reference statements)

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“…PD-L1 blockade by specific antibodies, which are currently approved treatment options for a broad range of cancer types [ 186 ], has noticeable effects on the CTL compartment, with enhanced tumor-specific cytotoxic activity and release of GzmB, Prf, and IFN-γ at the tumor site [ 187 ]. A report recently published by Yang and colleagues suggests the TIM-3 ligand Galectin-9 (Gal-9) as a target for immunotherapy based on the fact that (i) high Gal-9 expression correlates with poor prognosis in multiple human cancers [ 188 ], and (ii) in PD-1 + TIM-3 + T cells, PD-1 sequesters Gal-9, hampering its binding to TIM-3 with subsequent TIM-3-dependent T cell death, thereby contributing to the persistence of the exhausted T cell population [ 189 ].…”

Section: Discussionmentioning

confidence: 99%

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Capitani

Patrussi

Baldari

2021

IJMS

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Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

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Section: Discussionmentioning

confidence: 99%

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Capitani

Patrussi

Baldari

2021

IJMS

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“…Siglec-15, identified on antigen-presenting cells as an inhibitor of T cell activation, is targeted with an antibody in an early clinical trial for advanced solid tumors. Targeting Siglec-15 was tested in a system linked to the HER2-targeting antibody and an NK cell-mediated tumor cell killing was tested in vitro and in vivo [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

First Evidence for a Role of Siglec-8 in Breast Cancer

Trebo

Ditsch

Degenhardt

et al. 2021

IJMS

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Sialic acid-binding immunoglobulin-like lectins (Siglecs) are involved in various immune cell-mediated diseases. Their role in cancer is poorly investigated, and research focusses on Siglec-expression on immune cells interacting with tumor cells. This study evaluates the role of Siglec-8 in breast cancer (BC). Siglec-8 expression was analyzed immunohistochemically on 235 primary BC cases and was correlated with clinical and pathological parameters and outcome. Cell culture experiments were performed with various BC cell lines. Siglec-8 was expressed in 215 BC cases and expression was lowest in triple-negative BC. It correlated with estrogen receptor-status, grading and the prognostic factors galectin (Gal)-7 and tumor-associated mucin-1 (TA-MUC1). However, Gal-7 and TA-MUC1 were only prognosticators for clinical outcome in the cohort expressing high (Immunoreactivity score IRS > 3) Siglec-8 levels but not in the low-expressing cohort. Siglec-8 knockdown led to a significantly reduced Gal-7 expression in MCF7 cells. All BC cell lines expressed low Siglec-8-levels, that could be elevated in MCF7 by Peroxisome proliferator-activated receptor (PPARγ)-stimulation. This study demonstrates that Siglec-8 is expressed in BC cells and correlates with known clinical and prognostic parameters. It is probably associated with Gal-7 and TA-MUC1 and might be regulated via PPARγ. Further analyses focusing on functional associations will clarify Siglec-8’s eligibility as a possible therapeutic target.

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“…The involvement of multiple enzymes in glycan biosynthesis and their redundancy accounts for their stable expression and may diminish the risk of antigen escape. Tumor cells would indeed have to lose several of the >20 GalNAc polypeptide transferases that contribute to O-glycosylation to cease generating Tn antigen [60,61]. Glycoprotein expression may, however, still be lost if the proteins backbone were mutated (e.g.…”

Section: Target Selectionmentioning

confidence: 99%

CAR T cells: Building on the CD19 paradigm

et al. 2021

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Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B-cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence-associated pathologies.

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Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

Cited by 76 publications

References 178 publications

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

First Evidence for a Role of Siglec-8 in Breast Cancer

CAR T cells: Building on the CD19 paradigm

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