Search

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, represents a global health challenge due to its complexity and the limitations of current diagnostic techniques. By combining Raman spectroscopy and Artificial Intelligence (AI), we have succeeded in classifying tumor cells. In fact, we have performed a first Raman spectral analysis based on the characterization and differentiation between uncultured primary human liver cells derived from resected HCC tumor tissue and the adjacent non-tumor counterpart. Biochemical analysis of the collected Raman spectra revealed that there is more DNA in the nuclei of the tumor cells than in non-tumor cells. We then develop three machine learning approaches, including multivariate models and neural networks, to rapidly automate the recognition and classification of the Raman spectra of both cells. To evaluate the performance of the developed AI models, we prepared and analyzed two additional cell samples with a ratio of 4:1 and 3:1 between tumor and non-tumor cells and compared the obtained results with the nominal percentages (accuracy of 80 and 60%, respectively). These results confirm that the models are able to make classifications at the level of a single spectrum, indicating the possibility of rapidly analysing and classifying a primary HCC cell. more...

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach -reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides. [Display omitted] • Microbiome dynamic during immunotherapy correlates with clinical response in melanoma • Stable microbial functions carried by responders hold cross-cohort prognostic value • MHC class I peptides from stable flagellin-related genes mimic tumor-associated antigens • They induce reactivity on PBMC and TIL from responders and improve antitumor immunity Macandog et al. utilized longitudinal data to identify key gut microbial features in immunotherapy-responsive patients with melanoma. Functions stably carried by responders are specific to gut commensals that reportedly evolved mechanisms for human tolerance. These functions could provide advantage during immunotherapy by mimicking tumor antigens that stimulate effective tumor-clearing immunity. [ABSTRACT FROM AUTHOR] more...

Background: In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive CD8+ T cell can be elicited by the BNT162b2 preventive vaccine or the SARS-CoV-2 natural infection. Methods and results: Viral epitopes with high affinity (<100nM) to the HLAA* 02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and β chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining. Conclusions: Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop "multicancer" off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World. [ABSTRACT FROM AUTHOR] more...

Background: We have recently shown extensive sequence and conformational homology between tumor-associated antigens (TAAs) and antigens derived from microorganisms (MoAs). The present study aimed to assess the breadth of T-cell recognition specific to MoAs and the corresponding TAAs in healthy subjects (HS) and patients with cancer (CP). Method: A library of > 100 peptide-MHC (pMHC) combinations was used to generate DNA-barcode labelled multimers. Homologous peptides were selected from the Cancer Antigenic Peptide Database, as well as Bacteroidetes/Firmicutes-derived peptides. They were incubated with CD8 + T cells from the peripheral blood of HLA-A*02:01 healthy individuals (n = 10) and cancer patients (n = 16). T cell recognition was identified using tetramer-staining analysis. Cytotoxicity assay was performed using as target cells TAP-deficient T2 cells loaded with MoA or the paired TuA. Results: A total of 66 unique pMHC recognized by CD8+ T cells across all groups were identified. Of these, 21 epitopes from microbiota were identified as novel immunological targets. Reactivity against selected TAAs was observed for both HS and CP. pMHC tetramer staining confirmed CD8+ T cell populations cross-reacting with CTA SSX2 and paired microbiota epitopes. Moreover, PBMCs activated with the MoA where shown to release IFNγ as well as to exert cytotoxic activity against cells presenting the paired TuA. Conclusions: Several predicted microbiota-derived MoAs are recognized by T cells in HS and CP. Reactivity against TAAs was observed also in HS, primed by the homologous bacterial antigens. CD8+ T cells cross-reacting with MAGE-A1 and paired microbiota epitopes were identified in three subjects. Therefore, the microbiota can elicit an extensive repertoire of natural memory T cells to TAAs, possibly able to control tumor growth ("natural anti-cancer vaccination"). In addition, non-self MoAs can be included in preventive/therapeutic off-the-shelf cancer vaccines with more potent anti-tumor efficacy than those based on TAAs. [ABSTRACT FROM AUTHOR] more...