Selective Autophagy Conceals the Enemy: Why Cytotoxic T Cells Don’t (MH)C Pancreatic Cancer

Božić, Mihaela; Wilkinson, Simon

doi:10.1016/j.molcel.2020.06.009

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…Thus, our finding of LC3B expression in PD-L1+ immune cells in chordomas probably reflects starvation conditions and autophagic activation in these cellular subpopulations. It is worth noticing that autophagosomes and lysosomes have been found to contain major histocompatibility complex (MHC)-I molecules in pancreatic adenocarcinoma cells, preventing them from being expressed on the cell surface and thus from activating cytotoxic T cells [ 32 , 33 ]. Thus, our data add to the notion of autophagy being implicated in the immune tumor microenvironment and will prompt further investigation.…”

Section: Discussionmentioning

confidence: 99%

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Karpathiou

Dridi

Krebs-Drouot

et al. 2021

Cancers

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Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.

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Section: Discussionmentioning

confidence: 99%

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Karpathiou

Dridi

Krebs-Drouot

et al. 2021

Cancers

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“…This analysis further contributes to the growing body of evidence surrounding the role of autophagy inhibition in pancreatic cancer as an important therapeutic target, especially in the neoadjuvant setting. 36 , 37 A recent exciting study 38 and associated commentaries 39 , 40 , 41 , 42 , 43 , 44 , 45 have noted that enhanced autophagy in the setting of pancreatic cancer enables degradation of Class I major histocompatibility (MHC) molecules, critical for recognition by CD8+ T cells. Indeed, a previously published randomized study suggests that autophagy inhibition with HCQ promotes a much higher T‐cell infiltrate, consistent with a significant immune effect.…”

Section: Discussionmentioning

confidence: 99%

Encouraging long‐term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high‐risk patients with resectable pancreatic carcinoma

et al. 2021

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“…This kind of report suggests a role in managing the TME via antagonists of IL-1 and/or the JAK/STAT pathway. Further in PDAC, MHC-1 surface expression is frequently downregulated, possibly by mechanisms associated with autophagy ( 49 , 50 ). Finally, PDAC is a classic cold tumor where T-cells are actively excluded.…”

Section: Tumors With Extraordinary Tmes Pdac Gbm and Chlmentioning

confidence: 99%

Managing the TME to improve the efficacy of cancer therapy

2022

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The tumor microenvironment (TME) influences tumor growth, metastatic spread and response to treatment. Often immunosuppression, mediated by the TME, impairs a beneficial response. The complexity of the tumor composition challenges our abilities to design new and more effective therapies. Going forward we will need to ‘manage’ the content and or functionality of the TME to improve treatment outcomes. Currently, several different kinds of treatments are available to patients with cancer: there are the traditional approaches of chemotherapy, radiation and surgery; there are targeted agents that inhibit kinases associated with oncogenic pathways; there are monoclonal antibodies that target surface antigens often delivering toxic payloads or cells and finally there are antibodies and biologics that seek to overcome the immunosuppression caused by elements within the TME. How each of these therapies interact with the TME is currently under intense and widespread investigation. In this review we describe how the TME and its immunosuppressive components can influence both tumor progression and response to treatment focusing on three particular tumor types, classic Hodgkin Lymphoma (cHL), Pancreatic Ductal Adenocarcinoma (PDAC) and Glioblastoma Multiforme (GBM). And, finally, we offer five approaches to manipulate or manage the TME to improve outcomes for cancer patients.

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Selective Autophagy Conceals the Enemy: Why Cytotoxic T Cells Don’t (MH)C Pancreatic Cancer

Cited by 4 publications

References 10 publications

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Encouraging long‐term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high‐risk patients with resectable pancreatic carcinoma

Managing the TME to improve the efficacy of cancer therapy

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