Checkpoint inhibitor-associated autoimmunity

Ladak, Karim; Bass, Anne R.

doi:10.1016/j.berh.2019.03.009

Cited by 15 publications

(11 citation statements)

References 131 publications

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“…Similarly, aAbs against pancreatic islet antigens are frequently present in autoimmune type I diabetes; however, they are detected less often in patients that develop diabetes as a result of ICI. Autoimmune diseases also show a strong sex bias, but in inflammatory arthritis due to ICI, gender distribution was shown to be equal [ 71 ]. Therefore, there are similarities and differences between autoimmune diseases and irAE profiles.…”

Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

“…irAEs induced by anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies can show differences in frequency. For example, colitis and diarrhea as irAE are seen more often with anti-CTLA4 therapy than with anti-PD-1/PD-L1 therapy [ 71 ]. Hypothyroidism is also seen more frequently with the former therapy; however, it has been observed most frequently in the combinatorial therapy that includes both of the checkpoint molecules [ 71 ].…”

Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

“…For example, colitis and diarrhea as irAE are seen more often with anti-CTLA4 therapy than with anti-PD-1/PD-L1 therapy [ 71 ]. Hypothyroidism is also seen more frequently with the former therapy; however, it has been observed most frequently in the combinatorial therapy that includes both of the checkpoint molecules [ 71 ]. These differing irAEs can be due to the different mechanisms of negative regulation normally imposed by these molecules.…”

Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

See 2 more Smart Citations

Autoimmune Responses in Oncology: Causes and Significance

Bareke

Juanes-Velasco

Landeira-Viñuela

et al. 2021

IJMS

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Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

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Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

Section: Origins Of Autoimmune Responses In Oncologymentioning

confidence: 99%

See 1 more Smart Citation

Autoimmune Responses in Oncology: Causes and Significance

Bareke

Juanes-Velasco

Landeira-Viñuela

et al. 2021

IJMS

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“…Romatoid artrit fenotipi ve spondiloartropati fenotipi olmak üzere birçok şekilde kendini gösterebilmektedir. Altta yatan otoimmün hastalığın alevlenmesini önlemek için immün denetim noktası inhibitörleri ile tedaviden önce hastalara mevcut romatizmal hastalıklarına yönelik optimal tedavinin verilmesi önerilmektedir (25). Yan etkilerin oluşum mekanizmasına bakıldığında, tümör antijenine karşı artmış T hücre aktivitesinin tümoral doku gibi sağlıklı Gelişen bu yan etkilerle mücadelede ilaç dozunun azaltılması, ilaca ara verilmesi, steroid tedavisi gibi genel yaklaşımlar uygulanmaktadır.…”

Section: Yan Etkileriunclassified

Immune Checkpoints and Inhibitors

Aksu¹,

Şengül²

2020

atfm

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Günümüzde klinik önemi giderek artan tümör immünolojisi ile ilgili çalışmalar ilk olarak 19.yy'da William Coley'in ölü bakteri hücrelerini sarkomlara enjekte ederek tümör boyutlarında küçülme olduğunu göstermesiyle başlamıştır (1). Bu çalışmalar yeni tedavi yaklaşımlarının ve immün denetim noktalarını inhibe eden moleküller gibi yeni ajanların tüm kanser tiplerinde araştırılmasıyla sürmektedir. Klinik uygulamada karşımıza çıkan Antigen-specific T cells encountering and responding to tumor cells are regulated by a variety of mechanisms including inhibitory receptors and regulatory T cells to prevent overexposure immune responses. These regulatory mechanisms, so called ''immune checkpoints'', suppress T cell response. Thus, it prevents tissue damage and the development of autoimmunity by preventing an excessive immune response. Immune checkpoint inhibitors are increasingly used in clinical practice and have become part of the standard treatment approach for the treatment of various tumor types. These agents are antibody-based treatments targeting cytotoxic T-lymphocyte antigen-4, programmed cell death-1 and programmed cell death ligand-1. They have been used in the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, and some other tumor types. The incidence of toxicities has expanded with increasing clinical use. The side effects resulting from the immunological effects of these treatments are called ''immune-related adverse events'' and affect many organs in a wide spectrum, unlike conventional chemotherapy side effects. In order to understand the mechanisms of action and side effects of these therapies, which are more frequently encountered in clinical practice, it is necessary to understand immune checkpoints and inhibitors. In this review, receptors that function as immunological checkpoints, as well as the drugs targeting them, are described.

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“…Both the diversity and the high expression of inhibitory receptors by CD8 TILs (reviewed in [126]) can contribute to ICT resistance. However, combining blocking antibodies towards several inhibitory receptors to improve anti-tumor responses may further increase the adverse effects among which autoimmune attacks [127]. Therefore, manipulating CD8 T cells to resist local tumor-derived immune suppression may be of clinical benefit.…”

Section: Stat5 and Resistance To Immunosuppression In The Tumor Micromentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

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Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

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Checkpoint inhibitor-associated autoimmunity

Cited by 15 publications

References 131 publications

Autoimmune Responses in Oncology: Causes and Significance

Autoimmune Responses in Oncology: Causes and Significance

Immune Checkpoints and Inhibitors

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

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