An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Chinese Academy of Medical Sciences (CAMS); doi: https://doi.org/10.13039/501100005150Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design

Mechanisms of co-stimulatory and inhibitory receptors in human cancer-specific cytotoxic T cells

Clinical studies have shown that the upregulation of immunocheckpoints such as PD-1 on tumor-infiltrating T lymphocytes (TILs) can impair the clinical outcome of cancer patients. However, current immunocheckpoints-targeting immunotherapies have failed to improve response in some patients and cancer types. This is likely due to the heterogeneity of the tumor immune composition, the overall complex TILs immunophenotype and the influence of the immunosuppressive tumor microenvironment. It is therefore important to assess the characteristics and mechanisms of TILs, especially cancer-specific cytotoxic CD8+ T cells (CTLs), in order to develop more effective T cell immunotherapy strategies. In this study, comprehensive assessment using paired tumor, paratumor and peripheral blood from cancer patients demonstrated concomitant upregulation of both inhibitory CD94/NKG2a receptor and its HLA-E ligand in tumor. Although their engagement has been described on NK cells, it remains unclear whether this interaction could constitute an additional immunocheckpoint of cancer-specific CTLs in cancer. We demonstrated that the engagement of NKG2a and HLA-E resulted in impaired anti-tumor cytotoxicity, cytokine production and proliferation of CTLs, which recovered following antibody-blockade treatment. In contrast, the antagonistic NKG2a and CD103 expression on TILs suggest a distinct anti-tumor role of CD103. The CD103+ cancer-specific CTLs were found to self-produce TGF-β to sustain own CD103 expression, have improved TCR antigen sensitivity, faster cancer killing and elevated energy potential. However, they are more susceptible to apoptosis after prolonged cancer exposure. In addition, we demonstrated that a sizeable portion of cancer-specific CTLs lacks IFNγ expresssion and production, and discovered that this is contributed by CpG hypermethylation of its IFNγ promoter. In summary, this study carried out in-depth investigation into the impacts of the inhibitory receptor NKG2a, costimulatory receptor CD103, and epigenetic DNA methylation, on anti-tumor T cell responses. The thorough understanding of these key factors in affecting cancer-specific CTL functions and their restoration potential, could be important for future designs of more effective cancer immunotherapy strategies

Pleural fluid has pro-growth biological properties which enable cancer cell proliferation

Objectives: Patients with malignant pleural mesothelioma (MPM) or pleural metastases often present with malignant pleural effusion (MPE). This study aimed to analyse the effect of pleural fluid on cancer cells. Materials and Methods: Established patient-derived cancer cell cultures derived from MPE (MPM, breast carcinoma, lung adenocarcinoma) were seeded in 100% pleural fluid (exudate MPM MPE, transudate MPE, non-MPE transudate fluid) and proliferation was monitored. In addition, the establishment of new MPM cell cultures, derived from MPE specimens, was attempted by seeding the cells in 100% MPE fluid. Results: All established cancer cell cultures proliferated with similar growth rates in the different types of pleural fluid. Primary MPM cell culture success was similar with MPE fluid as with full culture medium. Conclusions: Pleural fluid alone is adequate for cancer cell proliferation in vitro, regardless of the source of pleural fluid. These results support the hypothesis that pleural fluid has important pro-growth biological properties, but the mechanisms for this effect are unclear and likely not malignant effusion specific.peer-reviewe