Tumor-infiltrating γδ T cells as targets of immune checkpoint blockade in melanoma.

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell-related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay.

Humoral and Cell-Mediated Responses to SARS-CoV-2 Vaccination in a Cohort of Immunodeficient Patients.

This study delves into the intricate landscape of SARS-CoV-2 vaccine response in immunodeficient patients, focusing on the dynamics of both humoral and cell-mediated immunity. The cohort includes patients with common variable immunodeficiency (CVI), agammaglobulinemia (XLA), and combined immunodeficiency (CI). The findings reveal varying degrees of antibody production, with XLA patients exhibiting no measurable response but displaying a robust T-cell-mediated response. The study emphasizes the importance of considering both arms of the immune system in assessing vaccine immunogenicity, particularly in the context of immunodeficiency. The results challenge conventional measures of vaccine efficacy only based on antibody titers, highlighting the need for a more comprehensive understanding of the immune response in this vulnerable population. This research contributes valuable insights to guide clinical decisions regarding vaccination strategies, booster doses, and overall protection in immunodeficient individuals.

Sicilian Semi- and Supercentenarians: Age-related NK Cell Immunophenotype and Longevity Trait Definition.

The immune system of semi- and supercentenarians (i.e., the oldest centenarians) is believed to have peculiar characteristics that enable them to reach extreme longevity in a relatively healthy state. Therefore, in previous papers, we investigated, through flow cytometry, variations in the percentages of the main subsets of Tαß and Tγδ cells in a Sicilian cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (>90 years old) and 8 oldest centenarians. These investigations suggested that some observed immunophenotypic changes may contribute to the extreme longevity of the oldest centenarians. In the present study, to further characterize the immunophenotype of the oldest centenarians, we examined the percentages of Natural Killer (NK) cells identified as CD3-CD56 + CD16+ in the previously described Sicilian cohort. We found a highly significant increase in NK cell percentages with age. When stratified by gender, this significant increase with age was maintained in both sexes, with higher significance observed in males. Our findings on NK cells, together with the previously obtained results, discussed in the context of the literature, suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune aging should be considered as a differential adaptation rather than a general immune alteration. These adapted immune mechanisms allow the oldest centenarians to successfully adapt to a history of insults and achieve remarkable longevity.

The Phenotypic Characterization of the Oldest Italian Man from December 28, 2020, to September 23, 2021, A.T., Strengthens the Idea That the Immune System can Play a Key Role in the Attainment of Extreme Longevity.

In this paper, we present demographic, clinical, anamnestic, cognitive, and functional data, as well as haematological, haematochemical, immunological, and genetic parameters of an exceptional individual: A.T., a semi-supercentenarian who held the title of the oldest living Italian male centenarian from 28 December 2020, to 23 September 2021. The purpose of this study is to provide fresh insights into extreme phenotypes, with a particular focus on immune-inflammatory parameters. To the best of our knowledge, this study represents the first phenotypic investigation of a semi-supercentenarian, illustrating both INFLA-score, a metric designed to assess the cumulative impact of inflammatory markers and indicators of age-related immune phenotype (ARIP), recognized as significant gauges of biological ageing. The aim of this study was, indeed, to advance our understanding of the role of immune-inflammatory responses in achieving extreme longevity. The results of laboratory tests, as well as clinical history and interview data, when compared to the results of our recent study on Sicilian centenarians, demonstrate an excellent state of health considering his age. Consistent with previous studies, we observed increased IL-6 inflammatory markers and INFLA score in A.T. More interestingly, the semi-supercentenarian showed values of ARIP indicators such as naïve CD4+ cells, CD4+/CD8+ ratio, and CD4+TN/TM ratio in the range of young adult individuals, suggesting that his immune system's biological age was younger than the chronological one. The results support the notion that the immune system can play a role in promoting extreme longevity. However, this does not rule out the involvement of other body systems or organs in achieving extreme longevity.