In a recent article, Sen Santara et al. demonstrated that the activating natural killer (NK) cell receptor NKp46 binds to externalized calreticulin (ecto‐CRT), leading to NK cell degranulation and ...target cell killing. They show that endoplasmic reticulum stress–induced ecto‐CRT serves as a danger‐associated molecular pattern, helping NK cells identify and eliminate infected, malignant, stressed or senescent cells.
The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of ...tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
Display omitted
•Dysfunctional CD226-negative T cells accumulate in mouse and human tumors•CD155 induces ubiquitination via CBL-B and proteasomal degradation of CD226•A mutation of Y319 maintains CD226 expression and improves anti-tumor immunity•ICB-therapy in melanoma patients relies on the presence of CD226+CD8+ T cells
Braun et al. find that CD155 on tumor cells drives the proteasomal degradation of the activating receptor CD226 on tumor-infiltrating CD8+ T cells, thus promoting immune evasion and resistance to cancer immunotherapy.
Plasticity of NK cells in Cancer Corvino, Dillon; Kumar, Ananthi; Bald, Tobias
Frontiers in immunology,
05/2022, Volume:
13
Journal Article
Peer reviewed
Open access
Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or
orchestration of the broader immune response. NK cells exist across a wide range ...of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.
The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a ...phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12
endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.
The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known ...oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1
transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.
BackgroundAmplification of the MYCN oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that MYCN promotes a ...non-inflamed and T-cell infiltration-poor (‘cold’) tumor microenvironment (TME) by suppressing interferon signaling. This may explain, at least in part, why patients with NB seem to have little benefit from single-agent immune checkpoint blockade (ICB) therapy. Targeting MYCN or its effectors could be a strategy to convert a cold TME into a ‘hot’ (inflamed) TME and improve the efficacy of ICB therapy.MethodsNB transcriptome analyses were used to identify epigenetic drivers of a T-cell infiltration-poor TME. Biological and molecular responses of NB cells to epigenetic drugs and interferon (IFN)-γ exposure were assessed by proliferation assays, immunoblotting, ELISA, qRT-PCR, RNA-seq and ChIP-qPCR as well as co-culture assays with T cells.ResultsWe identified H3K9 euchromatic histone-lysine methyltransferases EHMT2 and EHMT1, also known as G9a and GLP, as epigenetic effectors of the MYCN-driven malignant phenotype and repressors of IFN-γ transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-γ-induced expression of the Th1-type chemokines CXCL9 and CXCL10, key factors of T-cell recruitment into the TME. In MYCN-amplified NB cells, co-inhibition of EZH2 (enhancer of zeste homologue 2), a H3K27 histone methyltransferase cooperating with EHMTs, was needed for strong transcriptional responses to IFN-γ, in line with histone mark changes at CXCL9 and CXCL10 chemokine gene loci. EHMT and EZH2 inhibitor response gene signatures from NB cells were established as surrogate measures and revealed high EHMT and EZH2 activity in MYCN-amplified high-risk NBs with a cold immune phenotype.ConclusionOur results delineate a strategy for targeted epigenetic immunomodulation of high-risk NBs, whereby EHMT inhibitors alone or in combination with EZH2 inhibitors (in particular, MYCN-amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.
Objectives
Cellular immunity against BK polyomavirus (BKV)‐encoded antigens plays a crucial role in long‐term protection against virus‐associated pathogenesis in transplant recipients. However, ...in‐depth understanding on dynamics of these cellular immune responses is required to develop better immune monitoring and immunotherapeutic strategies.
Methods
Here, we have conducted a proteome‐wide analysis of BKV‐specific T‐cell responses in a cohort of 53 healthy individuals and 26 kidney transplant recipients to delineate the functional and transcriptional profile of these effector cells and compared these characteristics to T cells directed against cytomegalovirus, which is also known to cause significant morbidity in transplant recipients.
Results
Profiling of BKV‐specific CD4+ and CD8+ T cells revealed that kidney transplant recipients with high levels of circulating viraemia showed significantly reduced T‐cell reactivity against large T and/or small T antigens when compared to healthy donors. Interestingly, T cells specific for these antigens showed strong cross‐recognition to orthologous JC virus (JCV) peptides, including those exhibiting varying degrees of sequence identity. Ex vivo functional and phenotypic characterisation revealed that the majority of BKV‐specific T cells from renal transplant recipients expressed low levels of the key transcriptional regulators T‐bet and eomesodermin, which was coincident with undetectable expression of granzyme B and perforin. However, in vitro stimulation of T cells with BKV epitopes selectively enhanced the expression of T‐bet, granzyme B and cellular trafficking molecules (CCR4, CD49d and CD103) with minimal change in eomesodermin and perforin.
Conclusions
These observations provide an important platform for the future development of immune monitoring and adoptive T‐cell therapy strategies for BKV‐associated diseases in transplant recipients, which may also be exploited for similar therapeutic value in JCV‐associated clinical complications.
This manuscript provides comprehensive profiling of BK polyomavirus T‐cell responses in healthy virus carriers and kidney transplant recipients.
Objectives
There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. ...This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients.
Methods
CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated.
Results
Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen‐stimulated whole‐blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T‐cell subsets in asymptomatic individuals.
Conclusion
Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation‐induced tissue damage and subsequent disease in asymptomatic individuals.
We report the discovery of amphiregulin (AREG) as a distinguishing marker of CD4+ T cells from individuals with asymptomatic Leishmania donovani infection, compared to visceral leishmaniasis (VL) patients and healthy endemic control individuals. Thus, CD4+ T‐cell AREG is elevated during asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in asymptomatic individuals required for controlling infection and that AREG may play an important role in preventing inflammation‐induced tissue damage and subsequent disease in asymptomatic individuals.
PDF
