Immune Profiling of Thyroid Carcinomas Suggests the Existence of Two Major Phenotypes: an ATC-like and a PDTC-like

Giannini, Raffaello; Moretti, Sonia; Ugolini, Clara; Macerola, Elisabetta; Menicali, Elisa; Nucci, Nicole; Morelli, Silvia; Colella, Renato; Mandarano, Martina; Sidoni, Angelo; Panfili, Matteo; Basolo, Fulvio; Puxeddu, Efisio

doi:10.1210/jc.2018-01167

Cited by 57 publications

(75 citation statements)

References 54 publications

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“…The TCGA analysis allowed the classification of PTCs as “inflammatory” tumors because of the recognition of an important immune infiltrate [129] despite their well-known low mutational burden. Furthermore, an immune expression profiling of TC confirmed that mostly ATC and PTC show a microenvironment infiltrated by macrophages and CD8 + T-cells with a functionally exhausted appearance [130]. These reports support the possible classification of the ATC as hot and immunosuppressed tumor and encourage the use of OVs as potential therapeutic option.…”

Section: Future Treatments Based On Ovsmentioning

confidence: 72%

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Malfitano

Somma

Prevete

et al. 2019

Cancers

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Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed.

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Section: Future Treatments Based On Ovsmentioning

confidence: 72%

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Malfitano

Somma

Prevete

et al. 2019

Cancers

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“…Unfortunately, PDL1 immunostaining or other lymphocyte-related immunocytochemical characterizations were not performed on the FNAB verified adrenal metastasis, so we know little about the interaction between the metastatic ATC lesion and the immune system in this case. Interestingly, significant up-regulation of immune-related gene sets in ATCs compared to other thyroid cancer subtypes, including the immune checkpoint markers PDL1, PDL2, and PD1 have been reported [17]. Also, subsets of ATCs harbor gene amplifications of immune evasion genes, further acknowledging the importance of immune regulation in this disease [7].…”

Section: Discussionmentioning

confidence: 99%

Metastatic Anaplastic Thyroid Carcinoma in Complete Remission: Morphological, Molecular, and Clinical Work-Up of a Rare Case

et al. 2020

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Anaplastic thyroid carcinoma (ATC) exhibits an exceedingly poor prognosis, and the current treatment options are, for most cases, palliative by nature. Few reports of long-time survivors exist, although in these patients, tumors often were limited to the thyroid and/or regional lymph nodes. We describe a 64-year-old male who developed a rapidly growing mass in the left thyroid lobe. A fine-needle aspiration biopsy (FNAB) was consistent with ATC, and the patient underwent preoperative combined chemo-and radiotherapy followed by a hemithyroidectomy. The ensuing histopathological investigation was consistent with ATC adjoined by an oxyphilic well-differentiated lesion, likely a Hürthle cell carcinoma. Tumor margins were negative, and no extrathyroidal extension was noted. Focused next-generation sequencing analysis of the primary tumor tissue identified a TP53 gene mutation but could not identify any potential druggable targets. Additional Sanger sequencing detected a C228T TERT promoter mutation. The tumor was found to be microsatellite stable and displayed PDL1 expression in 80% of tumor cells. Following a CT scan 1 month postoperatively, metastatic deposits were suspected in the lung as well as in the left adrenal gland, of which FNAB verified the latter. Remarkably, upon radiological follow-up, the disease had gone into apparent complete remission. The patient is alive and well with no signs of residual disease after 12 months of follow-up. We here summarize the clinical, histological, and molecular data of this highly interesting patient case and review the literature for possible common denominators with other patients with disseminated ATC.

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“…TCGA analysis of TC provided a classi cation of PTC, in spite of their low mutational burden, as "in amed" tumours and ATC as hot tumours [38]. Interestingly, a pro ling of TC con rmed that ATC and PTC are strongly in ltrated by macrophages and CD8 + T cells, but that these cells displayed a functionally exhausted appearance [11]. In TC, high PD-L1 levels signi cantly correlated with immune in ltrate, increased tumour size and multifocality [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, aggressive forms of TC (PDTC and ATC) represent a clinic challenge displaying a remarkable chemo-and radio-resistant phenotype from the beginning [9,10]. Interestingly, aggressive forms of TC exhibit increased immune checkpoint expression and ine cient immune in ltrate [9,[11][12][13][14], features that are being evaluated for the treatment of the disease [9,14,15].…”

Section: Introductionmentioning

confidence: 99%

PD-1 Blockade Delays Tumor Growth by Inhibiting an Intrinsic SHP2/Ras/MAPK Signalling in Thyroid Cancer Cells

Liotti

Kumar

Prevete

et al. 2020

Preprint

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Background: The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).Methods: PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR; western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.Results: Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.Conclusions: PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

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Immune Profiling of Thyroid Carcinomas Suggests the Existence of Two Major Phenotypes: an ATC-like and a PDTC-like

Cited by 57 publications

References 54 publications

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Metastatic Anaplastic Thyroid Carcinoma in Complete Remission: Morphological, Molecular, and Clinical Work-Up of a Rare Case

PD-1 Blockade Delays Tumor Growth by Inhibiting an Intrinsic SHP2/Ras/MAPK Signalling in Thyroid Cancer Cells

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