Therapeutic treatments targeting communication between angiogenic and immune microenvironments in thyroid cancers

Hamidi S., Iyer P., Dadu R., Gule-Monroe M., Maniakas A., Zafereo M.E., Wang J.R., Busaidy N., Cabanillas M.

Petrik J., Lauks S., Garlisi B., Lawler J.

Many cancers begin with the formation of a small nest of transformed cells that can remain dormant for years. Thrombospondin-1 (TSP-1) initially promotes dormancy by suppressing angiogenesis, a key early step in tumor progression. Over time, increases in drivers of angiogenesis predominate, and vascular cells, immune cells, and fibroblasts are recruited to the tumor mass forming a complex tissue, designated the tumor microenvironment. Numerous factors, including growth factors, chemokine/cytokine, and extracellular matrix, participate in the desmoplastic response that in many ways mimics wound healing. Vascular and lymphatic endothelial cells, and cancer-associated pericytes, fibroblasts, macrophages and immune cells are recruited to the tumor microenvironment, where multiple members of the TSP gene family promote their proliferation, migration and invasion. The TSPs also affect the immune signature of tumor tissue and the phenotype of tumor-associated macrophages. Consistent with these observations, expression of some TSPs has been established to correlate with poor outcomes in specific types of cancer.

Soll D., Bischoff P., Frisch A., Jensen M., Karadeniz Z., Mogl M.T., Horst D., Penzkofer T., Spranger J., Keilholz U., Mai K.

Abstract Background Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. Methods In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. Results Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. Conclusions The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

Tan J.S., Tay T.K., Ong E.H., Fehlings M., Tan D.S., Sukma N.B., Chen E.X., Sng J., Yip C.S., Lim K.H., Lim D.W., Iyer N.G., Hwang J.S., Chua M.L., Ang M.

Objective Anaplastic thyroid cancer (ATC) is an aggressive disease associated with poor outcomes and resistance to therapies. Our study aim was to evaluate the activity of a combinatorial regimen of sandwich sequencing of pembrolizumab immunotherapy and hypofractionated radiotherapy (RT). Methods In this case series, patients with ATC received hypofractionated RT (QUAD-shot) and intravenous pembrolizumab 200 mg every 3–4 weeks. Pembrolizumab was continued until disease progression or up till 24 months. Concurrent lenvatinib treatment was allowed. Primary endpoint was best overall response (BOR) and progression-free survival (PFS). Additionally, we performed immune profiling of circulating T cells in a responder to investigate the immune response to our combinatorial treatment. Results At median follow-up of 32.6 months (IQR: 26.4–38.8), of a cohort of five patients, BOR was 80%; with two complete responses (CR) and two partial responses (PR). Patients who achieved CR remained disease-free at last follow-up. Median PFS was 7.6 months (IQR: 6.2–NR), and 1-year PFS and overall survival rate was 40% (95% CI: 13.7–100) for both. Treatment was well-tolerated, with mostly grade 1–2 adverse events. Immune profiling of one partial responder revealed an increase in activated CD4 and CD8 T cells post-QUAD-shot RT, which was further enhanced during the maintenance phase of pembrolizumab. Conclusion Herein, we report a case series of five patients with ATC, with two long-term survivors who were treated with surgical debulking followed by QUAD-shot RT and pembrolizumab, possibly due to synergy of local and systemic treatments in activating anti-tumour immunogenic cytotoxicity. This regimen warrants further investigation in a larger cohort of patients.

Kotwal A., Gustafson M.P., Bornschlegl S., Dietz A.B., Delivanis D., Ryder M.

BackgroundExploring the immune interface of follicular cell-derived thyroid cancer has prognostic and therapeutic potential. The available literature is lacking for comprehensive immunophenotyping in relation to clinical outcomes. In this study, we identify circulating immunophenotypes associated with thyroid cancer prognosis.MethodsWe conducted a pilot observational study of adults with follicular cell-derived thyroid cancer who underwent surgery at our tertiary care referral center and had consented for flow cytometry on peripheral blood collected at the time of thyroidectomy.ResultsOf the 32 included subjects, 20 (62%) had well differentiated, 5 (16%) had poorly differentiated, and 7 (22%) had anaplastic thyroid cancer. The most frequent AJCC stage was 4 (59%) and the ATA risk of recurrence category was high (56%). Patients with AJCC stage 3/4 demonstrated fewer circulating mononuclear cells (CD45+), more monocytes (CD14+), fewer total lymphocytes (CD14-), fewer T cells (CD3+), fewer CD4+ T cells, fewer gamma-delta T cells, fewer natural killer (NK) T-like cells, more myeloid-derived suppressor cells (MDSCs; Lin-CD33+HLADR-), and more effector memory T cells but similar CD8+ T cells compared to stage1/2. Immunophenotype comparisons by ATA risk stratification and course of thyroid cancer were comparable to those observed for stage, except for significant differences in memory T cell subtypes. The median follow-up was 58 months.ConclusionsAggressive follicular cell-derived thyroid cancer either at presentation or during follow-up is associated with down-regulation of the T cell populations specifically CD4+ T cells, gamma-delta T cells, and NK T-like cells but up-regulation of MDSCs and altered memory T cells. These immunophenotypes are potential prognostic biomarkers supporting future investigation for developing targeted immunotherapies against advanced thyroid cancer.

Tan J.K., Awuah W.A., Roy S., Ferreira T., Ahluwalia A., Guggilapu S., Javed M., Asyura M.M., Adebusoye F.T., Ramamoorthy K., Paoletti E., Abdul-Rahman T., Prykhodko O., Ovechkin D.

AbstractThyroid cancer, a prevalent form of endocrine malignancy, has witnessed a substantial increase in occurrence in recent decades. To gain a comprehensive understanding of thyroid cancer at the single-cell level, this narrative review evaluates the applications of single-cell RNA sequencing (scRNA-seq) in thyroid cancer research. ScRNA-seq has revolutionised the identification and characterisation of distinct cell subpopulations, cell-to-cell communications, and receptor interactions, revealing unprecedented heterogeneity and shedding light on novel biomarkers for therapeutic discovery. These findings aid in the construction of predictive models on disease prognosis and therapeutic efficacy. Altogether, scRNA-seq has deepened our understanding of the tumour microenvironment immunologic insights, informing future studies in the development of effective personalised treatment for patients. Challenges and limitations of scRNA-seq, such as technical biases, financial barriers, and ethical concerns, are discussed. Advancements in computational methods, the advent of artificial intelligence (AI), machine learning (ML), and deep learning (DL), and the importance of single-cell data sharing and collaborative efforts are highlighted. Future directions of scRNA-seq in thyroid cancer research include investigating intra-tumoral heterogeneity, integrating with other omics technologies, exploring the non-coding RNA landscape, and studying rare subtypes. Overall, scRNA-seq has transformed thyroid cancer research and holds immense potential for advancing personalised therapies and improving patient outcomes. Efforts to make this technology more accessible and cost-effective will be crucial to ensuring its widespread utilisation in healthcare.

Iesato A., Li S., Sadow P.M., Abbasian M., Nazarian A., Lawler J., Nucera C.

Oh D., Algazi A., Capdevila J., Longo F., Miller Jr W., Chun Bing J.T., Bonilla C.E., Chung H.C., Guren T.K., Lin C., Motola‐Kuba D., Shah M., Hadoux J., Yao L., Jin F., et. al.

Busaidy N.L., Konda B., Wei L., Wirth L.J., Devine C., Daniels G.A., DeSouza J.A., Poi M., Seligson N.D., Cabanillas M.E., Sipos J.A., Ringel M.D., Eisfeld A., Timmers C., Shah M.H.

Background: Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer (DTC), and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib + trametinib therapy in patients with BRAF-mutated radioactive iodine refractory DTC. Methods: In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory DTC with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 13 months before enrollment were eligible. Patients were randomly assigned to receive dabrafenib alone or dabrafenib + trametinib. The primary endpoint was objective response rate by modified RECIST (minor response of -20% to -29%, partial and complete response) within the first 24 weeks of therapy. Trial Registration Number: NCT01723202. Results: A total of 53 patients were enrolled. The objective response rate (modified RECIST) was 42% (11/26 [95% confidence interval {CI} 23-63%]) with dabrafenib versus 48% (13/27 [CI 29-68%]) with dabrafenib + trametinib (p = 0.67). Objective response rate (RECIST 1.1) was 35% (9/26 [CI 17-56%]) with dabrafenib and 30% (8/27 [CI 14-51%]) with dabrafenib + trametinib. Most common treatment-related adverse events included skin and subcutaneous tissue disorders (17/26, 65%), fever (13/26, 50%), hyperglycemia (12/26, 46%) with dabrafenib alone and fever (16/27, 59%), nausea, chills, fatigue (14/27, 52% each) with dabrafenib + trametinib. There were no treatment-related deaths. Conclusions: Combination dabrafenib + trametinib was not superior in efficacy compared to dabrafenib monotherapy in patients with BRAF-mutated radioiodine refractory progressive DTC.

Wang Y., Sun Q., Ye Y., Sun X., Xie S., Zhan Y., Song J., Fan X., Zhang B., Yang M., Lv L., Hosaka K., Yang Y., Nie G.

Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here, we report that an elevation of FGF-2 signaling in samples from patients with nasopharyngeal carcinoma (NPC) and xenograft mouse models promoted NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1/AHR signaling. Gain- and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization toward an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposome treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2/FGFR1/pericyte/CXCL14/TAM stromal communication axis in NPC and propose an effective antimetastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2hi tumors.

Román-Gil M.S., Pozas J., Rosero-Rodríguez D., Chamorro-Pérez J., Ruiz-Granados Á., Caracuel I.R., Grande E., Molina-Cerrillo J., Alonso-Gordoa T.

Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.

Subbiah V., Kreitman R.J., Wainberg Z.A., Cho J.Y., Schellens J.H., Soria J.C., Wen P.Y., Zielinski C.C., Cabanillas M.E., Boran A., Ilankumaran P., Burgess P., Romero Salas T., Keam B.

Pizzato M., Li M., Vignat J., Laversanne M., Singh D., La Vecchia C., Vaccarella S.

Thyroid cancer incidence rates have increased in many countries and settings; however, mortality rates have remained stable at lower rates. This epidemiological pattern has been largely attributed to an overdiagnosis effect. Timely evidence for the global epidemiological status is necessary to identify the magnitude of this problem and the areas mostly affected by it. We therefore aimed to provide an up-to-date assessment on the global distribution of thyroid cancer incidence and mortality rates in 2020.We extracted age-standardised incidence and mortality rates per 100 000 person-years of thyroid cancer as defined by the International Classification of Diseases for Oncology 10th Revision (code C73), for 185 countries or territories by sex and 18 age groups (ie, 0-4, 5-9, …, 80-84, and ≥85 years) from the GLOBOCAN database. Both incidence and mortality estimates were presented by country and aggregated across the 20 UN-defined world regions and according to the UN's four-tier Human Development Index (ie, low, medium, high, and very high) in 2020.Globally, in 2020, the age-standardised incidence rates of thyroid cancer were 10·1 per 100 000 women and 3·1 per 100 000 men, and age-standardised mortality rates were 0·5 per 100 000 women and 0·3 per 100 000 men. In both sexes, incidence rates were five times higher in high and very high Human Development Index countries than in low and medium Human Development Index countries, whereas mortality rates were relatively similar across different settings. Incidence rates in women differed by more than 15 times across world regions, with the highest incidence rates being in the Federated States of Micronesia and French Polynesia (18·5 per 100 000 women), North America (18·4 per 100 000), and east Asia (17·8 per 100 000, with South Korea reaching 45 per 100 000). Mortality rates were less than one per 100 000 in most countries and in both sexes. South Korea had the highest incidence-to-mortality rate ratio in both sexes, followed by Cyprus and Canada.The current thyroid cancer epidemiological landscape is strongly suggestive of a large effect of overdiagnosis in many countries and settings worldwide, confirming the relevance of thyroid cancer overdiagnosis as a global public health problem.None.

Pu W., Shi X., Yu P., Zhang M., Liu Z., Tan L., Han P., Wang Y., Ji D., Gan H., Wei W., Lu Z., Qu N., Hu J., Hu X., et. al.

The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications. The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.

Dahlberg J., Adok C., Bümming P., Demir A., Hedbäck G., Nilsson B., Nilsson M., Jansson S.

Abstract Background It is unclear whether the increasing incidence of thyroid cancer (TC) due to increased diagnosis of small and indolent tumours might mask a real increase of clinically significant cancers. The aim of this study was to correlate surgery, pathology and outcome data of individual patients to the mode of primary detection (palpation, by imaging or incidental) to assess if TC incidence has increased. Methods The Swedish Cancer Registry identified all patients with TC in Västra Götaland County representing approximately 1.6 million inhabitants. Clinical information was retrieved from medical records of patient cohorts from three study intervals (2001–2002, 2006–2007 and 2011–2014) comprising 60 per cent of all TC patients. Data were also obtained from the NORDCAN registry to compare of TC incidence with other Nordic countries. Results Between 2001 and 2014, the annualized standard incidence rate/100 000 population (ASR) of TC increased from 3.14 to 10.71 in women and from 1.12 to 3.77 in men. This was higher than the mean incidence for Sweden but similar to that in Norway and Finland. Differentiated TC (DTC) increased more than threefold. The majority of tumours (64 per cent) were detected by palpation. Larger tumours (10–20, 21–40 and greater than 40 mm) increased as much as microcarcinomas (less than 10 mm). Only 5 per cent of the tumours were detected by imaging. All disease-specific deaths (8.5 per cent of DTC in the first two cohorts) and most patients with recurrent or persistent disease (6.6 per cent of DTC cases) were diagnosed due to tumour-related symptoms. Conclusion DTC in Western Sweden gradually increased between 2001 and 2014. The majority of tumours were detected by palpation suggesting a real increase in the incidence of clinically significant thyroid malignancies.