Where Do We Stand with Immunotherapy for Advanced Pancreatic Ductal Adenocarcinoma: A Synopsis of Clinical Outcomes

Akhuba, L. G.; Тигай, Ж. Г.; Shek, Dmitrii

doi:10.3390/biomedicines10123196

Cited by 8 publications

(4 citation statements)

References 66 publications

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“…Immune checkpoint inhibitors have demonstrated limited clinical benefits in PDAC compared to other cancers [ 54 ]. While therapeutic DNA cancer vaccination approaches targeting tumor associated antigens have been explored as a promising strategy, especially for patients unresponsive to immune checkpoint inhibitors [ 55 , 56 ], these approaches have yielded limited patient responses in clinical trials, particularly in the context of PDAC.…”

Section: Discussionmentioning

confidence: 99%

Immunization with a multi-antigen targeted DNA vaccine eliminates chemoresistant pancreatic cancer by disrupting tumor-stromal cell crosstalk

Qin,

Chen,

Bouchekioua-Bouzaghou

et al. 2023

J Transl Med

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Background Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting the tumor-stromal cell crosstalk is considered as an improved PDAC treatment strategy, whereas little progress has been made due to poor understanding of its underlying mechanism. Here, we examined the cellular role of melanoma associated antigen A isoforms (MAGEA) in regulating tumor-stromal crosstalk mediated chemoresistance. Methods We used clinical samples to explore the correlation between MAGEA expression and patient prognosis in multiple cancers. We utilized cancer cell lines, patient derived organoids and orthotopic PDAC model to examine the function of MAGEA in chemoresistance. We performed biochemical, proteome profiler array and transcriptional analysis to uncover a mechanism that governs tumor-stromal crosstalk. We developed a multi-MAGEA antigen targeted DNA vaccine and tested its effect on PDAC tumor growth. Results We establish MAGEA as a regulator of the tumor-stromal crosstalk in PDAC. We provide strong clinical evidence indicating that high MAGEA expression, including MAGEA2, MAGEA3 and MAGEA10, correlates with worse chemotherapeutic response and poor prognosis in multiple cancers, while their expression is up-regulated in chemoresistant PDAC patient derived organoids and cancer cell lines. Mechanistically, MAGEA2 prohibits gemcitabine-induced JNK-c-Jun-p53 mediated cancer cell apoptosis, while gemcitabine stimulated pancreatic stellate cells secretes GDF15 to further enhance the gemcitabine resistance of MAGEA2 expressing cells by activating GFRAL-RET mediated Akt and ERK1/2 dependent survival pathway. Strikingly, immunization with a DNA vaccine that targeting multiple MAGEA antigens, including MAGEA2, MAGEA3 and MAGEA10, elicits robust immune responses against the growth of gemcitabine resistant tumors. Conclusions These findings suggest that targeting MAGEA-mediated paracrine regulation of chemoresistance by immunotherapy can be an improved pancreatic cancer treatment strategy.

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Section: Discussionmentioning

confidence: 99%

Immunization with a multi-antigen targeted DNA vaccine eliminates chemoresistant pancreatic cancer by disrupting tumor-stromal cell crosstalk

Qin,

Chen,

Bouchekioua-Bouzaghou

et al. 2023

J Transl Med

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“…The standard treatment care for PC in clinical practice is the application of combination chemotherapy (131,132). Conventional chemotherapy offers a low 5-year survival rate due to its limited efficacy and suboptimal response (133). Patients with DNA repair dysfunction, including BRCA mutations, benefit from platinum chemotherapy and PARP inhibitors (31).…”

Section: Discussionmentioning

confidence: 99%

A pancreatic adenocarcinoma mimicking hepatoid carcinoma of uncertain histogenesis: A case report and literature review

Iliesiu,

Toma,

Ciongariu

et al. 2023

Oncol Lett

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In rare cases, metastatic adenocarcinomas of different origin may exhibit the features of hepatoid carcinoma (HC), a rare malignant epithelial tumor, most commonly occurring in the ovaries and stomach, as well as in the pancreas and biliary ducts. A case of a 72-year-old female patient who developed a highly aggressive, poorly differentiated pancreatic ductal adenocarcinoma with peritoneal carcinomatosis, demonstrating hepatoid differentiation upon conventional hematoxylin and eosin staining is reported in the present study. The patient presented with severe abdominal pain, and the radiological investigations performed revealed ovarian and hepatic tumor masses and peritoneal lesions, which were surgically removed. The gross examination of the peritoneum and omentum revealed multiple solid, firm, grey-white nodules, diffusely infiltrating the adipose tissue. The microscopic examination revealed a malignant epithelial proliferation, composed of polygonal cells with abundant eosinophilic cytoplasm and irregular, pleomorphic nuclei. Certain cells presented with intracytoplasmic mucus inclusions, raising suspicion of a HC with an uncertain histogenesis. Immunohistochemical staining was performed, and the tumor cells were found to be positive for cytokeratin (CK)7, CK18 and mucin 5AC, whereas negative staining for CK20, caudal-type homeobox transcription factor 2, α-fetoprotein, paired box gene 8, GATA-binding protein 3 and Wilms tumor 1 were documented. Thus, the diagnosis of metastatic pancreatic adenocarcinoma was established. The main aim of the present study was to provide further knowledge concerning poorly differentiated metastatic adenocarcinoma resembling HC, emphasizing the histopathological and immunohistochemical features of these malignant lesions and raising awareness of the diagnostic difficulties that may arise, as well as the importance of the use immunohistochemistry in differentiating carcinomas of uncertain histogenesis.

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“…Immune checkpoint inhibitors and second-generation hormonal treatments have been associated, particularly in PDAC, with resistance to enzalutamide due to an increased expression of PD-L1 in dendritic cells, despite the controversial immunomodulatory role of the new hormonal therapies [126].…”

Section: Selected Clinical Trials Providing Information On Ici Combin...mentioning

confidence: 99%

Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

Lauriola

Davalli

Marverti

et al. 2023

Cancers

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Immunotherapy is a cancer treatment that exploits the capacity of the body’s immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies yet. Within the field of cancer immunotherapy, an expansion of the combination strategy that targets independent cellular pathways that can work synergistically is predicted. Here, we review some consequences of tumor cell death and increased immune system engagement in the modulation of oxidative stress and ubiquitin ligase pathways. We also indicate combinations of cancer immunotherapies and immunomodulatory targets. Additionally, we discuss imaging techniques, which are crucial for monitoring tumor responses during treatment and the immunotherapy side effects. Finally, the major outstanding questions are also presented, and directions for future research are described.

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Where Do We Stand with Immunotherapy for Advanced Pancreatic Ductal Adenocarcinoma: A Synopsis of Clinical Outcomes

Cited by 8 publications

References 66 publications

Immunization with a multi-antigen targeted DNA vaccine eliminates chemoresistant pancreatic cancer by disrupting tumor-stromal cell crosstalk

Immunization with a multi-antigen targeted DNA vaccine eliminates chemoresistant pancreatic cancer by disrupting tumor-stromal cell crosstalk

A pancreatic adenocarcinoma mimicking hepatoid carcinoma of uncertain histogenesis: A case report and literature review

Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

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