Exosomes in melanoma: A role in tumor progression, metastasis and impaired immune system activity

Exosomes (Exo) are small vesicles produced by melanoma cells and the accessory cells of the tumor microenvironment. They emerge via both classical and direct pathways and actively participate in tumor colonisation of distant tissues. The proteins, nucleic acids, cytokines and growth factors engulfed by Exo are transferred to recipient cells, where they drive numerous functions required for the tumor escape from immune system control and tumor progression. By positively or negatively modulating immune cell properties, Exo provoke immune suppression and, in turn, defective dendritic cell (DC) functions. Together, these effects limit the cytotoxicity of T-cells and expand both T-regulatory and myeloid-derived suppressor populations. They also hinder perforin and granzyme production by natural killer cells. Finally, Exo also control the organotropism of melanoma cells. The distinct phenotypic properties of Exo can be exploited both for diagnostic purposes and in the early identification of melanoma patients likely to respond to immunotherapy. The potential therapeutic application of Exo derived from DCs has been demonstrated in vaccination trials, which showed an increase in anti-melanoma activity with respect to circulating tumor cells. However, additional studies are required before Exo can be effectively used in diagnostic and therapeutic applications in melanoma

Adding Concomitant Chemotherapy to Postoperative Radiotherapy in Oral Cavity Carcinoma with Minor Risk Factors: Systematic Review of the Literature and Meta-Analysis

Simple Summary Oral cavity carcinoma (OCC) is the 11th most frequently diagnosed cancer; despite a multimodal treatment, locally advanced OCC, managed by surgery and adjuvant therapies, remains at high risk of recurrence, with a 5-year overall survival (OS) of 51%. The efficacy of postoperative chemotherapy in addition to radiotherapy (POCRT) in low-intermediate risk OCC is a controversial matter in the absence of high-risk features (ENE, R1). To establish the role of POCRT in a population with solely minor risk factors (perineural invasion or lymph vascular invasion; pN1 single; DOI >= 5 mm; close margin; node-positive level IV or V; pT3 or pT4; multiple lymph nodes without ENE), we performed a systematic review and meta-analyses focused on OS, disease-free survival (DFS), and local-recurrence-free survival (LRFS). Thirteen studies met the inclusion criteria and were included in the quantitative meta-analyses. Our preliminary results are in favor of POCRT in terms of OS but not conclusive for DFS and LRFS. Further analyses are suggested. When presenting with major pathological risk factors, adjuvant radio-chemotherapy for oral cavity cancers (OCC) is recommended, but the addition of chemotherapy to radiotherapy (POCRT) when only minor pathological risk factors are present is controversial. A systematic review following the PICO-PRISMA methodology (PROSPERO registration ID: CRD42021267498) was conducted using the PubMed, Embase, and Cochrane libraries. Studies assessing outcomes of POCRT in patients with solely minor risk factors (perineural invasion or lymph vascular invasion; pN1 single; DOI >= 5 mm; close margin < 2-5 mm; node-positive level IV or V; pT3 or pT4; multiple lymph nodes without ENE) were evaluated. A meta-analysis technique with a single-arm study was performed. Radiotherapy was combined with chemotherapy in all studies. One study only included patients treated with POCRT. In the other 12 studies, patients were treated with only PORT (12,883 patients) and with POCRT (10,663 patients). Among the patients treated with POCRT, the pooled 3 year OS rate was 72.9% (95%CI: 65.5-79.2%); the pooled 3 year DFS was 70.9% (95%CI: 48.8-86.2%); and the pooled LRFS was 69.8% (95%CI: 46.1-86.1%). Results are in favor of POCRT in terms of OS but not significant for DFS and LRFS, probably due to the heterogeneity of the included studies and a combination of different prognostic factors

CORRIGENDUM to The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma

In this article, the authors’ first names and surnames were incorrectly listed in the wrong order. The correct author list is: Marco Tucci, Anna Passarelli, Annalisa Todisco, Francesco Mannavola, Luigia Stefania Stucci, Stella D’Oronzo, Michele Rossini, Marco Taurisano, Loreto Gesualdo and Franco Silvestris

Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients

none24noIntroduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/ tumor sample, are available. We aimed to evaluate the prognostic value of K-Ras mutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.openVincenzi B.; Cremolini C.; Sartore-Bianchi A.; Russo A.; Mannavola F.; Perrone G.; Pantano F.; Loupakis F.; Rossini D.; Ongaro E.; Bonazzina E.; Dell'Aquila E.; Imperatori M.; Zoccoli A.; Bronte G.; Maglio G.D.; Fontanini G.; Natoli C.; Falcone A.; Santini D.; Onetti-Muda A.; Siena S.; Tonini G.; Aprile G.Vincenzi, B.; Cremolini, C.; Sartore-Bianchi, A.; Russo, A.; Mannavola, F.; Perrone, G.; Pantano, F.; Loupakis, F.; Rossini, D.; Ongaro, E.; Bonazzina, E.; Dell'Aquila, E.; Imperatori, M.; Zoccoli, A.; Bronte, G.; Maglio, G. D.; Fontanini, G.; Natoli, C.; Falcone, A.; Santini, D.; Onetti-Muda, A.; Siena, S.; Tonini, G.; Aprile, G

Prognostic significance of KRAS mutation rate in metastatic colorectal cancer patients.

No abstract availabl

DLC-1 down-regulation via exosomal miR-106b-3p exchange promotes CRC metastasis by the epithelial-to-mesenchymal transition

Exosomes (Exo) have emerged as potent amplifiers of pro-tumorigenic signals to distant cells. The knowledge of their role in colorectal cancer (CRC) is continuously up-growing, although their contribution to metastasis remains largely unclear. Liu et al. (Clinical Science (2020) 134, https://doi.org/10.1042/CS20191087) in their work have described a novel mechanism by which CRC-derived Exo promote metastasis through the down-regulation of the deleted in liver cancer-1 (DLC-1), a gene involved in the epithelial-to-mesenchymal transition (EMT) event in cancer cells. The Authors also demonstrated an increase in serum exosomal miR-106b-3p in patients with metastatic CRC, suggesting its potential implication as a prognostic biomarker. These findings may be of great effort in clarifying the underlying mechanisms of CRC metastasis and provide new targets for future researches

The metabolic milieu in melanoma: Role of immune suppression by CD73/adenosine

The mechanisms leading to immune escape of melanoma have been largely investigated in relation to its tumour immunogenicity and features of inflamed microenvironment that promote the immune suppression during the disease progression. These findings have recently led to advantages in terms of immunotherapy-based approaches as rationale for overcoming the immune escape. However, besides immune checkpoints, other mechanisms including the adenosine produced by ectonucleotidases CD39 and CD73 contribute to the melanoma progression due to the immunosuppression induced by the tumour milieu. On the other hand, CD73 has recently emerged as both promising therapeutic target and unfavourable prognostic biomarker. Here, we review the major mechanisms of immune escape activated by the CD39/CD73/adenosine pathway in melanoma and focus potential therapeutic strategies based on the control of CD39/CD73 downstream adenosine receptor signalling. These evidences provide the basis for translational strategies of immune combination, while CD73 would serve as potential prognostic biomarker in metastatic melanoma

Abstract 2012: In vitro validation of tumor-derived large extracellular vesicles isolation and characterization as suitable tool for liquid biopsy

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Massive hyper-progression during anti-PD1 immunotherapy in a young patient with metastatic mucinous adenocarcinoma of the right colon: a case report and literature review

Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape of both solid and hematological malignancies, including tumors historically considered “non-immunogenic”, such as colorectal cancer (CRC). The increasing use of immunotherapy brought to light novel patterns of response due to its intrinsic mechanism of action. Besides the “pseudo-progression”, another peculiar phenomenon linked to ICIs activity is the “hyper-progression” (HP), namely a paradoxical disease acceleration during immunotherapy. This event, which suggests potentially deleterious effects of immunotherapy, has not been yet completely understood and lacks strict definition criteria, pathogenetic characterization as well as predictive factors. In this report, we present a case of an atypical massive progression in a 40-years old man with metastatic mucinous right colon cancer harboring high microsatellites instability (MSI-H), occurring after 2 cycles of pembrolizumab as first line therapy. Unfortunately, he experienced a widespread cancer dissemination for massive bone colonization and both numerical and volumetric increase of pre-existing node metastasis associated with rapid clinical worsening, which were suggestive for HP. To our knowledge, this is one of the few cases of HP in metastatic CRC that has been reported, particularly with a so rapid clinical deterioration and massive skeletal involvement. Other experiences and further studies are warranted to better understand this phenomenon and anticipate its recognition

Liquid Biopsy as a Tool Exploring in Real-Time Both Genomic Perturbation and Resistance to EGFR Antagonists in Colorectal Cancer

The treatment of metastatic colorectal cancer (mCRC) has improved since the introduction of the epithelial growth factor receptor (EGFR) inhibitors as cetuximab and panitumumab. However, only patients with peculiar genomic profiles benefit from these targeting therapies. In fact, the molecular integrity of RAS genes is a predominant factor conditioning both primary and acquired resistance in non-responders although additional molecular derangements induced by selective anti-EGFR pressure may concur to the failure of those disease treatment, liquid biopsy (LB) appears as a surrogate of tissue biopsy, provides the genomic information to reveal tumor resistance to anti-EGFR agents, the detection of minimal residual disease before adjuvant therapies, and the discovery of tumor molecular status suitable for rechallenging treatments with EGFR antagonists. LB investigates circulating tumor cells (CTCs), cell-free tumor DNA (ctDNA), and tumor-derived exosomes. In mCRC, ctDNA analysis has been demonstrated as a useful method in the mutational tracking of defined genes as well as on tumor burden and detection of molecular alterations driving the resistance to anti-EGFR targeting treatments. However, despite their efficiency in molecular diagnosis and prognostic evaluation of mCRC, the affordability of these procedures is prevalently restricted to research centers, and the lack of consensus validation prevents their translation to clinical practice. Here, we revisit the major mechanisms responsible for resistance to EGFR blockade and review the different methods of LB potentially useful for treatment options in mCRC