Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer

Zhou

et al. 2017

Sci Rep

Pancreatic cancer is one of the most aggressive malignancies and has a highly immunosuppressive tumour microenvironment. Immune checkpoint blockade has led to remarkable and durable objective responses in a number of malignancies and antibody-based strategies targeting programmed cell death protein 1 (PD-1) are showing promise where traditional modalities of surgery, radiotherapy, and chemotherapy have failed. In this study, we examined the clinical value of PD-1 protein expression by CD8+ peripheral T lymphocytes or tumour-infiltrating T lymphocytes (TILs) in pancreatic ductal adenocarcinoma (PDAC). Expression of PD-1 protein on CD8+ TILs correlated with overall survival and clinicopathological characteristics such as clinical stage, N classification, and M classification. Similar findings were observed for the expression of PD-1 protein on peripheral CD8+ T cells, whereas its expression on peripheral CD4+ T cells showed no significance. Comparison of the levels of PD-1 protein expressed by peripheral CD8+ T cells before and 4 weeks after surgery indicated that preoperative and postoperative status of peripheral PD-1 expression was unchanged. Our findings showed that PD-1 protein expressed by peripheral or tumour-infiltrated CD8+ T cells was a promising biomarker for diagnosis and prognosis in PDAC and might help guide future immunotherapies.

Section: Discussionmentioning

confidence: 99%

Prognostic value of programmed cell death protein 1 expression on CD8+ T lymphocytes in pancreatic cancer

Zhou

et al. 2017

Sci Rep

Clinical & Translational Med

“…Particularly in melanoma and lung cancers, patients enjoy longer survival, and in rare cases, complete remission in response to immunotherapy [195,196]. Immunotherapy for pancreatic cancer has not yet shown the same degree of success, but many have chronicled the progress thus far in detailed reviews [197–200]. Single‐agent immunotherapy clinical trials in human PDA have particularly been ineffective, thought in part to be due to decreased PD‐1/PD‐L1 expression compared to other tumors, but many ongoing studies are examining combinations, including with cytotoxic chemotherapy and radiation [75,201].…”

Section: Future Directionsmentioning

confidence: 99%

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Daniel

Sullivan

Labadie

et al. 2019

165

109

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.

“…However, most clinical trials on checkpoint inhibition in patients with pancreatic carcinoma had disappointing outcomes 139. A study on CTLA-4 antibody ipilimumab in 27 patients with metastatic or locally advanced pancreatic carcinoma found no statistically significant beneficial efficacy 140.…”

Section: Introductionmentioning

confidence: 99%

“…A study on CTLA-4 antibody ipilimumab in 27 patients with metastatic or locally advanced pancreatic carcinoma found no statistically significant beneficial efficacy 140. Most clinical trials on combination of anti-PD-1 monoclonal antibodies (mAbs) nivolumab and pembrolizumab, with chemotherapies such as gemcitabine, nab-paclitaxel or irinotecan have not yet been published 139. Results on anti-PD-L1 treatment in pancreatic cancer have been reported141; however, no conclusive beneficial evidence has been reported yet for the patient populations investigated in those trials (current trials are listed in online supplementary table 2).…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Neeße

Bauer

Öhlund

et al. 2018

Gut

269

245

Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.