Fas ligand–mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas

Afshar‐Sterle, Shoukat; Zotos, Dimitra; Bernard, Nicholas J.; Scherger, Anna Katharina; Rödling, Lisa; Alsop, Amber E.; Walker, Jennifer; Masson, Frédérick; Belz, Gabrielle T.; Corcoran, Lynn M.; O’Reilly, Lorraine A.; Strasser, Andreas; Smyth, Mark J.; Johnstone, Ricky W.; Tarlinton, David M.; Nutt, Stephen L.; Kallies, Axel

doi:10.1038/nm.3442

Cited by 85 publications

(86 citation statements)

References 76 publications

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“…In fact, it was recently shown that Tc cells use FasL to eradicate transplanted B-cell lymphoma cells in RAG1 (recombination activating gene 1)-deficient mice (47). This result confirms previous findings using animals with natural mutations in Fas (lpr) or FasL (gld; refs.…”

Section: Cancer Immunosurveillancesupporting

confidence: 90%

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Martínez-Lostao

Anel

Pardo

2015

Clinical Cancer Research

574

439

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In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed.

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Section: Cancer Immunosurveillancesupporting

confidence: 90%

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Martínez-Lostao

Anel

Pardo

2015

Clinical Cancer Research

574

439

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“…T cells play an important role in suppressing spontaneous B-cell lymphoma (36) and are prominent features of the FL microenvironment. We found that T cells that were infiltrating CREBBP mutant FL tumors showed transcriptional signatures of decreased T-cell proliferation, suggesting the CREBBP mutation-associated decreases in MHC class II result in lower levels of T-cell stimulation.…”

Section: Discussionmentioning

confidence: 99%

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

322

372

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Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. lymphoma | exome | hierarchy | antigen presentation | CREBBP

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“…Indeed, it has been proposed that FasL-driven CD8 C T cell killing could be essential for the elimination of large and/or disseminated tumors. [33][34][35] However, it should be noted that tumors can lose Fas expression or develop mutations in the cell death pathway engaged by FasL, thus developing resistance to FasL/Fas-mediated CD8 C T cell cytotoxicity. Other mechanisms by which tumors can resist CD8 C T cell cytotoxicity are increased expression of anti-apoptotic molecules such as Bcl -2, Bcl -xl, and Mcl -1 and changes in components of the cytoskeleton that impair the formation of stable immunological synapses between cytotoxic CD8…”

Section: Cd8mentioning

confidence: 99%