PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

Ozawa, Naoya; Yokobori, Takehiko; Osone, Katsuya; Katayama, Chika; Suga, Kunihiko; Komine, Chika; Shibasaki, Yuta; Shiraishi, Takeshi; Okada, Takuhisa; Kato, Ryuji; Ogawa, Hiroomi; Sano, Akihiko; Sakai, Makoto; Sohda, Makoto; Ojima, Hitoshi; Miyazaki, Tatsuya; Motegi, Yoko; Ide, Munenori; Yao, Takashi; Kuwano, Hiroyuki; Shirabe, Ken; Saeki, Hiroshi

doi:10.1038/s41598-021-92530-3

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…We have shown that PD-1, PD-L1 and A2aR signalling confers OAC cells with a survival advantage as their blockade alone reduces OAC cell viability and can enhance FLOT chemotherapy toxicity. Of relevance, studies have implicated a role for PD-L1 intrinsic signalling in mediating DNA repair in colon cancer 40 . Therefore, to achieve a greater understanding of the mechanisms of action behind enhanced FLOT cytotoxicity in combination with ICB we assessed if blockade of these IC pathways might alter the formation of γH2AX alone and in combination with FLOT chemotherapy (Fig.…”

Section: Resultsmentioning

confidence: 99%

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PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

Davern

Brien

McGrath

et al. 2022

Sci Rep

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Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.

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Section: Resultsmentioning

confidence: 99%

“…PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colon cancer 40 . Furthermore, several studies have shown that accumulation of damaged DNA and subsequent DNA damage signalling mediates upregulation of PD-L1 on the surface of tumour cells 18 , 55 , 56 .…”

Section: Discussionmentioning

confidence: 99%

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

Davern

Brien

McGrath

et al. 2022

Sci Rep

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“…The PD-1 and PD-L1 may not be associated with disease progression in patients with TNBC, but the level rate of PD-1 and PD-L1 in TNBC tissues was significantly higher than that in non-TNBC, which suggested that PD-1 and PD-L1 had potential involvement in the development of TNBC [7] . PD-L1 disease is expressed in various solid malignancies, including melanoma and lung, bladder, colon, pancreatic as well as head and neck cancers [8,9,10,11] . PD-1 also acts to suppress lymphocytes, thereby limiting autoimmunity by inhibiting PD-L1 [12] .…”

Section: Pd-1 Expression and Therapy In Tnbcmentioning

confidence: 99%

PD-1/PD-L1 Correlates with the Progression of Triple Negative Breast Cancer

2023

JCMP

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As a common female disease, breast cancer is mostly found in premenopausal and postmenopausal fair sexs, Its attack shows an increasing year by -year and younger trend [1] . Its molecular classification by immunohistochemistry and FISH is classified as Luminal A, Luminal B, Triple negative, HER-2-overexpressing, and especially Triple Negative Breast Cancer (TNBC), which is the most malignant form, accounting for about 15% of all infiltrative breast cancers and confers an grew hazard [2,3,4] . Since the pathological hallmarks of TNBC are mainly the expression of all receptors for ER ( estrogen receptor), PR (progesterone receptor), and HER-2 (human epidermal growth factor receptor 2), there is probably a high lack of specificity, and there is no target for early treatment of this type of disease, Even more challenging to be treated than some other breast cancer with endocrine therapy or targeted therapy, and relatively low chance of survival and uncomplicated metastasis in five years, so it is also a significant treatment conundrum for advanced breast cancer in the future that can hardly be breached, The main reason is that it is the PD-1 (programmed death-1) receptor and its part PD-L1 ( programmed death ligand 1) are highly expressed in TNBC patients relative to other different types of breast cancer, and are involved in the immune escape mechanism of tumor cells, if the immune mechanism involved by PD-1 is inhibited, for the treatment of TNBC there will be essential progress, more and more studies found that, The immune system and its T cells have an significant role in clearing tumor cells, and in this review, we discuss the mechanisms between PD-1/PD-L1 and TNBC, as well as clinical applications for treating TNBC.

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“…In humans, it was shown that patients with UC-associated dysplasia and cancer had increased expression of the PD-1 ligand PD-L1 on CD8 + T cells, as compared to sporadic CRC. PD-L1 overexpression correlated to chronic inflammation-induced DNA damage, and PD-L1 upregulation was mediated by inflammation-induced upregulation of IRF-1 [ 198 ] ( Table 1 ). Whether this exhaustion phenotype on T cells also leads to decreased effector functions of T cells, and thus interferes with their immunosurveillance function, needs further investigation.…”

Section: The Role Of the Immune System In Ibd-associated Cancermentioning

confidence: 99%

The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

Frigerio

Lartey

D’Haens

et al. 2021

IJMS

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Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.

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PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

Cited by 10 publications

References 47 publications

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

PD-1/PD-L1 Correlates with the Progression of Triple Negative Breast Cancer

The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

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