Extratumoral PD-1 blockade does not perpetuate obesity-associated inflammation in esophageal adenocarcinoma

Galvin, Karen; Conroy, Melissa J.; Doyle, Suzanne; Dunne, Margaret R.; Fahey, Ronan; Foley, Emma; O’Sullivan, Katie E.; Doherty, Derek G.; Geoghegan, Justin; Ravi, Narayanasamy; O’Farrelly, Cliona; Reynolds, John V.; Lysaght, Joanne

doi:10.1016/j.canlet.2018.01.039

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…No differences in PD-1 expression were detected in a preliminary analysis comparing n = 4 unmatched pre-treatment and post-treatment tumors (data not shown). This differs from earlier observations by our colleagues, who note a loss of PD-1 in OAC tumor T cells post-treatment (53), however greater numbers of patients are needed to confirm this finding, ideally in matched patient samples at pre- and post-treatment time points. MAIT cells have previously been reported to be exempt from the deleterious effects of chemotherapy, unlike other T cell subsets (3).…”

Section: Discussioncontrasting

confidence: 99%

Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma

et al. 2019

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Oesophageal adenocarcinoma (OAC) is an aggressive malignancy with poor prognosis, and incidence is increasing rapidly in the Western world. Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites and kill infected cells, yet their role in OAC is unknown. We aimed to elucidate the role of MAIT cells during cancer development by characterizing the frequency, phenotype, and function of MAIT cells in human blood and tissues, from OAC and its pre-malignant inflammatory condition Barrett's oesophagus (BO). Blood and tissues were phenotyped by flow cytometry and conditioned media from explanted tissue was used to model the effects of the tumor microenvironment on MAIT cell function. Associations were assessed between MAIT cell frequency, circulating inflammatory markers, and clinical parameters to elucidate the role of MAIT cells in inflammation driven cancer. MAIT cells were decreased in BO and OAC blood compared to healthy controls, but were increased in oesophageal tissues, compared to BO-adjacent tissue, and remained detectable after neo-adjuvant treatment. MAIT cells in tumors expressed CD8, PD-1, and NKG2A but lower NKG2D than BO cohorts. MAIT cells produced less IFN-γ and TNF-α in the presence of tumor-conditioned media. OAC cell line viability was reduced upon exposure to expanded MAIT cells. Serum levels of chemokine IP-10 were inversely correlated with MAIT cell frequency in both tumors and blood. MAIT cells were higher in the tumors of node-negative patients, but were not significantly associated with other clinical parameters. This study demonstrates that OAC tumors are infiltrated by MAIT cells, a type of CD8 T cell featuring immune checkpoint expression and cytotoxic potential. These findings may have implications for immunotherapy and immune scoring approaches.

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Section: Discussioncontrasting

confidence: 99%

Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma

et al. 2019

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“…This may also be one of the mechanisms [171]. However, two clinical trials have shown that PD-1 immunotherapy after radiation therapy can cause an excessive immune response, as seen in the adverse effects of combination therapy in obesity-related malignancies, including esophageal adenocarcinoma [182,183]. This may be because the relationship between radiation and the immune system is complex and multifactorial, and is related to the dose and type of radiation and the type of immune cells [181].…”

Section: Combination Therapeutic Strategy For Combined Chemoradiotherapymentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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“…The zebra plot (Figures 8D,E) and the pseudocolor plot with smoothing (Figure S5) clearly showed that more cells stained positive with the PD-1 mAb than the control isotype control IgG. The PD-1 mAb clone EH12.EH7 (Biolegend) used in the current study has been used previously by other investigators to detect PD-1 expression on CD8 + T cells in lymph nodes of SIV-infected rhesus macaques (62) and in esophageal carcinomas in humans (63). These data demonstrate that the reactivity of the PD-1 mAb is specific.…”

Section: Discussionmentioning

confidence: 68%

Cannabinoid Attenuation of Intestinal Inflammation in Chronic SIV-Infected Rhesus Macaques Involves T Cell Modulation and Differential Expression of Micro-RNAs and Pro-inflammatory Genes

et al. 2019

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Cannabis use is frequent in HIV-infected individuals for its appetite stimulation and anti-inflammatory effects. To identify the underlying molecular mechanisms associated with these effects, we simultaneously profiled micro-RNA (miRNA) and mRNA expression in the colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques administered either vehicle (VEH/SIV; n = 9) or Δ 9 -tetrahydrocannabinol (Δ 9 -THC; THC/SIV; n = 8). Pro-inflammatory miR-130a, miR-222, and miR-29b, lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV rhesus macaques. Compared to VEH/SIV rhesus macaques, 10 miRNAs were significantly upregulated in THC/SIV rhesus macaques, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV rhesus macaques. Moreover, THC/SIV rhesus macaques failed to upregulate pro-inflammatory miR-21, miR-141 and miR-222, and alpha/beta-defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV rhesus macaques showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13 , keratin-8 (stress protection), PROM1 (epithelial proliferation), and anti-HIV CCL5 . Gomori one-step trichrome staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but not in THC/SIV rhesus macaques, thus demonstrating the ability of Δ 9 -THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that Δ 9 -THC suppressed intestinal T cell proliferation/activation (Ki67/HLA-DR) and PD-1 expression and increased the percentages of anti-inflammatory CD163 + macrophages. Finally, while Δ 9 -THC did not affect the levels of CD4 + T cells, it significantly reduced absolute CD8 + T cell numbers in peripheral blood at 14 and 150 days post-SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in Δ 9 -THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

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Extratumoral PD-1 blockade does not perpetuate obesity-associated inflammation in esophageal adenocarcinoma

Cited by 11 publications

References 27 publications

Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma

Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Cannabinoid Attenuation of Intestinal Inflammation in Chronic SIV-Infected Rhesus Macaques Involves T Cell Modulation and Differential Expression of Micro-RNAs and Pro-inflammatory Genes

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