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BackgroundMelanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation.MethodsWe used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders.ResultsOur study identifies two CD8+TRM subsets, TCF1+ and TCF1−, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1− TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1− subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1− TRM/cDC1 pairs in tumor areas. Notably, these TCF1− TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1− TRM subsets, alongside cDC1, prove relevant to CBI response.ConclusionsOur study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1− TRM subsets, both crucial for melanoma control and CBI response.

Immunotherapy has improved the clinical response in melanoma patients, although a relevant percentage of patients still cannot be salvaged. The search for the immune populations that provide the best tumor control and that can be coaxed by immunotherapy strategies is a hot topic in cancer research nowadays. Tumor-infiltrating TCF-1 progenitor exhausted CD8 T cells seem to grant the best melanoma prognosis and also efficiently respond to anti-PD-1 immunotherapy, giving rise to a TIM-3 terminally exhausted population with heightened effector activity. We tested Porins from Typhi as a pathogen associated molecular pattern adjuvant of natural or model antigen in prophylactic and therapeutic immunization approaches against murine melanoma. Porins induced protection against melanomas, even upon re-challenging of tumor-free mice. Porins efficiently expanded IFN-γ-producing CD8 T cells and induced central and effector memory in lymph nodes and tissue-resident (Trm) T cells in the skin and tumors. Porins induced TCF-1 PD-1 CD8 Trm T cells in the tumor stroma and the presence of this population correlated with melanoma growth protection in mice. Porins immunization also cooperated with anti-PD-1 immunotherapy to hamper melanoma growth. Importantly, the potentially protective Trm populations induced by Porins in the murine model were also observed in melanoma patients in which their presence also correlated with disease control. Our data support the use of cancer vaccination to sculpt the tumor stroma with efficient and lasting Trm T cells with effector activities, highlighting the use of Porins as an adjuvant. Furthermore, our data place CD8 Trm T cells with a progenitor exhausted phenotype as an important population for melanoma control, either independently or in cooperation with anti-PD-1 immunotherapy.

Background Cancer has been defined as a group of diseases that result from the uncontrolled growth of abnormal cells that form tumors, invade nearby tissues, and spread to other parts of the body. The notion of “uncontrolled” growth, however, would imply that cancer cells grow following no biological rules and without any regulation. Yet, evidence presented over the past three decades, based on genomic, epigenetic, molecular, cellular, immunologic, and physiological approaches, indicates that cancer is, for the most part, a controlled, although abnormal, process that results in the formation of solid tumors or hematologic neoplasms. Cancer seems to be a hybrid process in which stochastic events coexist with constraining and regulatory influences. The present article is an up-to-date comprehensive overview on the current evidence supporting the notion that, although cancer implies abnormal -malignant- cellular growth, it is not uncontrolled cellular growth. Herein, we summarize and discuss the evidence indicating that cancer originates and progresses under the action and influence of specific factors and mechanisms that regulate, in a finely way, tumor cell growth and dissemination. Conclusion While cancer manifests as abnormal cell growth, it cannot and should not be reduced to a set of uncontrolled processes. On the contrary, multiple biological mechanisms interact in a precise and coordinated manner, akin to the pieces of a Rubik’s cube, which do not align by chance, but rather as the result of a synchronized sequence of events. To conceive cancer merely as unregulated cell proliferation is to underestimate and misrepresent the nature of such an assembled disease.

Side population (SP) and ABC transporter expression enrich for stem cells in numerous tissues. We explored if this phenotype characterised human bladder cancer stem cells (CSCs) and attempted to identify regulatory mechanisms. Focusing on non-muscle invasive bladder cancer (NMIBC), multiple human cell lines were used to characterise SP and ABC transporter expression. In vitro and in vivo phenotypic and functional assessments of CSC behaviour were undertaken. Expression of putative CSC marker ABCG2 was assessed in clinical NMIBC samples (n = 148), and a role for MAPK signalling, a central mechanism of bladder tumourigenesis, was investigated. Results showed that the ABCG2 transporter was predominantly expressed and was up-regulated in the SP fraction by 3-fold (ABCG2(hi)) relative to the non-SP (NSP) fraction (ABCG2(low)). ABCG2(hi) SP cells displayed enrichment of stem cell markers (Nanog, Notch1 and SOX2) and a three-fold increase in colony forming efficiency (CFE) in comparison to ABCG2(low) NSP cells. In vivo, ABCG2(hi) SP cells enriched for tumour growth compared with ABCG2(low) NSP cells, consistent with CSCs. pERK was constitutively active in ABCG2(hi) SP cells and MEK inhibition also inhibited the ABCG2(hi) SP phenotype and significantly suppressed CFE. Furthermore, on examining clinical NMIBC samples, ABCG2 expression correlated with increased recurrence and decreased progression free survival. Additionally, pERK expression also correlated with decreased progression free survival, whilst a positive correlation was further demonstrated between ABCG2 and pERK expression. In conclusion, we confirm ABCG2(hi) SP enriches for CSCs in human NMIBC and MAPK/ERK pathway is a suitable therapeutic target.

Background Approximately 50% of cases of penile carcinoma (PeCa), a rare neoplasm worldwide, are associated with human papillomavirus (HPV). However, the detection of HPV-DNA is not sufficient to consider it the etiological factor in the development of this type of cancer. Currently, the overexpression of P16INK4A is used as a surrogate biomarker of HPV carcinogenesis. Information on PeCa in Mexico is scarce, particularly regarding cases related to HPV and genotype frequency. Objective To evaluate the presence of HPV, its genotypes, and the presence of multiple genotypes, and the expression of P16INK4A, as well as its clinical and histopathological parameters. Methods For HPV-DNA detection and P16INK4A expression, we used the INNO-LiPA® test and immunohistochemistry, respectively. Results Sixty cases of PeCa were evaluated, of which 75% were HPV-non-related histological variants. We found that 58.9% (33/56) of PeCa cases were HPV-DNA positive, while 30.9% of the cases evaluated (17/55) were positive for P16INK4A. HPV16 was the main genotype in 42.9% of the cases, followed by HPV52 in 7.1% and HPV18 in 5.4%. Within the HPV-positive cases, 27.3% had multiple genotypes. All HPV-positive patients under the age of 45 years were positive only for HPV16. Conclusions HPV16 was the most commonly detected genotype in PeCa. HPV 31, 35 and 39 were infrequent; however, they were related to a single infection and P16INK4A overexpression; thus, they seem to be relevant in PeCa carcinogenesis. Our results suggest that P16INK4A overexpression could be useful for the classification of HPV-related PeCa. The role of multiple HPV genotypes in the development and prognosis of PeCa is still not completely understood. Thus, it is necessary to define criteria to establish reliable ways to classify HPV-related PeCa that could lead to optimal therapeutic approaches.

Objective Mediastinal schwannomas are sometimes confused with other neoplasms during initial radiological studies, especially when there is a history of cancer in another area. In these cases, a more accurate analysis using computed tomography (CT) or even magnetic resonance (MRI) is required. Our study aimed to perform a retrospective analysis of the clinical and imaging features for a series of patients with mediastinal schwannomas that were confirmed by histology and immunohistochemistry. Results We found eight patients, five men and three women, with an average age of 51 years for this study. The main signs and symptoms at diagnosis were chest pain, dyspnea, cough, and dysphagia. CT showed that the tumor was located in the posterior compartment of the chest in 7/8 cases. Tumors > 10 cm were more heterogeneous and showed cystic changes. All patients underwent posterolateral thoracotomy, and radiological follow-up showed no evidence of recurrence. Histological analysis was considered the gold standard to confirm diagnosis, along with at least one neurogenic IHC marker. In conclusion, mediastinal schwannomas are benign encapsulated tumors. According to CT, schwannomas > 10 cm show cystic degeneration more frequently. Posterolateral thoracotomy allows complete resection and is considered the surgical approach of choice.

[This corrects the article on p. 205 in vol. 8, PMID: 28337194.].

Long non-coding RNAs (lncRNAs) are key regulators of gene expression, that can regulate a range of carcinogenic processes. Moreover, they exhibit stability in biological fluids, with some displaying tissue specificity. As their expression depends on specific conditions or is linked to the regulation of particular signaling pathways, lncRNAs are promising candidates for providing insights into the likely progression of the disease. This allows for the stratification of patients based on their risk of progression, making them potential prognostic biomarkers in various types of cancer. In addition, the tissue-specific expression profile of lncRNAs renders them ideal candidates for detection, prognosis and monitoring of cancer progression. The present study aims to provide an overview of differentially expressed lncRNAs in Mexican patients with triple-negative breast cancer (TNBC), a subtype of breast cancer. The aim was to identify potential prognostic biomarkers that can be applied to improve the clinical management of Mexican patients with TNBC. Human Transcriptome Array 2.0 microarrays were used to analyze the transcriptome of TNBC and luminal tumors, which are reported to have a good prognosis amongst aggressive tumor types. Subsequently, results from these microarrays were validated in a cohort from The Cancer Genome Atlas, an independent cohort of Mexican patients and in breast cancer cell lines (MCF7, ZR75, T47D, MDA-MB-231, MDA-MB-468 and BT20). A total of 746 differentially expressed transcripts were identified, including 102 lncRNAs in TNBC compared with luminal tumors. Among the lncRNAs with the most significant changes in expression levels, SOX9-AS was highly expressed in TNBC, whereas the expression of Lnc-peroxidasin-3:1 (Lnc-PXDN-3:1), Lnc-RNA Synapse Defective Rho GTPase Homolog (Lnc-SYDE) and long intergenic non-coding RNA (LINC)01087 were decreased. In addition, the low expression of lncRNA LINC01087, LINC02568, ACO22196, and lncRNA eosinophil granule ontogeny transcript (Lnc-EGOT) was associated with poor overall survival (OS). Further analysis revealed that the high expression levels of Lnc-PXDN-3:1, Lnc RNA fibrous sheath interacting protein 1-6:3 and (LINC)00182 were associated with reduced survival in patients with the luminal subtype of breast cancer. Similarly, low expression levels of lncRNAs such as GATA binding protein 3-1 (Lnc-GATA-3-1), LINC01087, and BX679671.1 in luminal subtypes of breast cancer, as well as LINC00504 and LncRNA rho guanine nucleotide exchange factor 38 intronic transcript 1 (Lnc-ARHGEF38-IT1) in basal subtypes have been linked to poorer survival. The interactions and functions of LINC01087 were then investigated, revealing the interaction of LINC01087 with RNAs and transcription factors, highlighting their potential involvement in the estrogen receptor pathway. The present study provided a detailed analysis of the expression of lncRNAs in TNBC, which highlights the role of lncRNAs as a biomarker in the survival outcomes of patients with breast cancer to improve the understanding of transcriptional regulation in TNBC.

Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.

We aimed to characterize microbiota of the gastric mucosa as it progress to intestinal type of cancer. Study included five patients each of non-atrophic gastritis (NAG), intestinal metaplasia (IM) and intestinal-type gastric cancer (GC). Gastric tissue was obtained and DNA extracted for microbiota analyses using the microarray G3 PhyloChip. Bacterial diversity ranged from 8 to 57 and steadily decreased from NAG to IM to GC (p = 0.004). A significant microbiota difference was observed between NAG and GC based on Unifrac-presence/absence and weighted-Unifrac-abundance metrics of 283 taxa (p < 0.05). HC-AN analyses based on presence/absence of 238 taxa revealed that GC and NAG grouped apart, whereas IM overlapped with both. An ordinated analyses based on weighted-Unifrac distance given abundance of 44 taxa showing significance across categories revealed significant microbiota separation between NAG and GC. This study is the first to show a gradual shift in gastric microbiota profile from NAG to IM to GC.