Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

Maggio, Ilaria; Manuzzi, Lisa; Ricci, Angela Dalia; Tober, Nastassja; Campana, Davide

doi:10.3390/cancers12040832

Cited by 30 publications

(30 citation statements)

References 111 publications

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“…This also suggests an important role for immune modulation in GEP-NENs and DNA methylation might be a mechanism to regulate the gene expression of these proteins. Multiple studies evaluating immunotherapy in well-differentiated GEP-NENs are ongoing, but so far, observed response rates have been low [45,46]. Possible explanations are the cold immune microenvironment, i.e., the lack of immune cells, which might be caused by the described immune modulation in GEP-NENs resulting in immune evasion, and the low tumor mutational burden in GEP-NENs, as a high tumor mutational burden has been shown to associate with an increased benefit of immunotherapy [47].…”

Section: Discussionmentioning

confidence: 99%

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance.

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Section: Discussionmentioning

confidence: 99%

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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“…Although MSI-H was reported to be 0% in PNETs [ 67 ], 3.6% in NETs [ 10 ] and 12.4% in NECs [ 151 ], ICIs may be effective in high-grade NETs and NECs based on preliminary results from a few clinical trials [ 152 ]. The phase 2 DART SWOG 1609 study aims to evaluate the efficacy of the nivolumab plus ipilimumab in patients with rare tumors and reported an RR of 13% (2/15) in patients with previously treated, non-pancreatic GI NETs [ 61 ]; the PNET cohort is accruing.…”

Section: Gi Neuroendocrine Neoplasmsmentioning

confidence: 99%

Management of Non-Colorectal Digestive Cancers with Microsatellite Instability

Zhu

Jin

Hubbard

2021

Cancers

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Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.

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“…NETs are relatively rare tumors, representing less than 0.5% of all malignant tumors, although their diagnosis has increased in recent years, probably due to improved awareness. Most of these tumors are benign, but 12% to 22% present with distant metastases [ 154 , 155 ].…”

Section: Potential Role Of Icis In Rare Vulvar Tumor Typesmentioning

confidence: 99%

“…Regarding Merkel cell carcinoma, important results have been obtained with the use of ICIs; indeed, the FDA has approved avelumab and pembrolizumab for their treatment, whereas the European Medicine Agency has approved avelumab only [ 155 ], but unfortunately results concerning vulvar Merkel cell carcinomas have never been reported [ 161 , 162 , 163 , 164 ].…”

Section: Potential Role Of Icis In Rare Vulvar Tumor Typesmentioning

confidence: 99%

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

Borella

Preti

Bertero

et al. 2020

IJMS

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Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

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Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

Cited by 30 publications

References 111 publications

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Management of Non-Colorectal Digestive Cancers with Microsatellite Instability

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

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