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Nature Dec 2023CD8 cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity, with precursor exhausted T (T) cells but not terminally exhausted T...
CD8 cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity, with precursor exhausted T (T) cells but not terminally exhausted T (T) cells capable of responding to existing immunotherapies. The gene regulatory network that underlies CTL differentiation and whether T cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation. First, the exit from quiescence of T cells initiated successive differentiation into intermediate T cells. This process is differentially regulated by IKAROS and ETS1, the deficiencies of which dampened and increased mTORC1-associated metabolic activities, respectively. IKAROS-deficient cells accumulated as a metabolically quiescent T cell population with limited differentiation potential following immune checkpoint blockade (ICB). Conversely, targeting ETS1 improved antitumour immunity and ICB efficacy by boosting differentiation of T to intermediate T cells and metabolic rewiring. Mechanistically, TCF-1 and BATF are the targets for IKAROS and ETS1, respectively. Second, the RBPJ-IRF1 axis promoted differentiation of intermediate T to terminal T cells. Accordingly, targeting RBPJ enhanced functional and epigenetic reprogramming of T cells towards the proliferative state and improved therapeutic effects and ICB efficacy. Collectively, our study reveals that promoting the exit from quiescence of T cells and enriching the proliferative T cell state act as key modalities for antitumour effects and provides a systemic framework to integrate cell fate regulomes and reprogrammable functional determinants for cancer immunity.
Topics: Humans; Cell Differentiation; Clustered Regularly Interspaced Short Palindromic Repeats; Gene Editing; Immune Checkpoint Inhibitors; Mutagenesis; Neoplasms; Single-Cell Analysis; T-Lymphocytes, Cytotoxic
PubMed: 37968405
DOI: 10.1038/s41586-023-06733-x -
Pharmacology & Therapeutics Feb 2018Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy... (Review)
Review
Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials. In this review, we have compiled the worldwide effort in exploring T cell engaging bispecific antibodies. Our special emphasis is on the lessons learned, with the hope to derive insights in this fast evolving field with tremendous clinical potential.
Topics: Animals; Antibodies, Bispecific; Humans; Immunity, Innate; Models, Biological; Neoplasms; T-Lymphocytes, Cytotoxic
PubMed: 28834699
DOI: 10.1016/j.pharmthera.2017.08.005 -
The Journal of Clinical Investigation Sep 2015The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory... (Review)
Review
The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell effector function following initial activation by costimulatory signals. Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and antitumor responses in patients with advanced metastatic melanoma. Responses observed with such immune checkpoint therapy can follow a different pattern from that seen with cytotoxic chemotherapy or targeted therapy and may continue after therapy is discontinued. In addition, the toxicities that are associated with anti-CTLA-4 therapy may differ from those of conventional therapies and consist of inflammatory events in parts of the body that do not contain cancerous cells. Early recognition of these inflammatory events and intervention is important, and the identification of predictive biomarkers continues to be an unfulfilled need in the field of immunotherapy. Combinatorial approaches with targeted therapies, radiation therapy, chemotherapy, or other immune checkpoint agonists/antagonists have the potential to increase the efficacy of CTLA-4 blockade.
Topics: Animals; Antibodies, Monoclonal; CTLA-4 Antigen; Cell Cycle Checkpoints; Humans; Melanoma; Neoplasm Metastasis; T-Lymphocytes, Cytotoxic
PubMed: 26325034
DOI: 10.1172/JCI80012 -
Cell Mar 2016The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting...
The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals.
Topics: Animals; Biomechanical Phenomena; Cell Degranulation; Cell Line, Tumor; Immunological Synapses; Mice; Perforin; Phosphatidylinositol 3-Kinases; T-Lymphocytes, Cytotoxic
PubMed: 26924577
DOI: 10.1016/j.cell.2016.01.021 -
Seminars in Cell & Developmental Biology Jul 2021Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required for host defense. They destroy malignant target cells like cancer cells. Among metal cations, Ca... (Review)
Review
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required for host defense. They destroy malignant target cells like cancer cells. Among metal cations, Ca plays a prescinded role for CTL and NK cytotoxicity as it is the only cation used as ubiquitous second messenger. Measuring intracellular Ca concentrations [Ca] in single cells has greatly changed our understanding of Ca signaling. Yet, comparing the role of Ca in the pre-[Ca] and [Ca] measurement era reveals that even in the pre-[Ca] measurement era (before 1980), the functions of Ca and some other metal cations for the cytotoxic immune response were well established. It was even shown that Ca influx across the plasma membrane but not Ca release from intracellular sources is relevant for lymphocyte cytotoxicity and that very little Ca is needed for efficient lymphocyte cytotoxicity against cancer cells. In the [Ca] measurement era after 1980, many of the important findings were better and more quantitatively refined and in addition the molecules important for Ca transport were defined. The unexpected finding that there is a Ca optimum of CTL and NK cell cytotoxicity deserves some attention and may be important for anti-cancer therapy.
Topics: Calcium; Humans; Killer Cells, Natural; T-Lymphocytes, Cytotoxic
PubMed: 33358089
DOI: 10.1016/j.semcdb.2020.12.002 -
Journal of Biomedicine & Biotechnology 2010
Topics: Humans; T-Lymphocytes, Cytotoxic; Vaccines
PubMed: 21049005
DOI: 10.1155/2010/936549 -
JCI Insight Feb 2020Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular...
Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ-JAK1/2-STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus-infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.
Topics: Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Fatty Acids; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Mice; Mice, Knockout; Signal Transduction; T-Lymphocytes, Cytotoxic; Up-Regulation
PubMed: 32102981
DOI: 10.1172/jci.insight.133393 -
Frontiers in Immunology 2021Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of...
Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8 T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca-dependent manner.
Topics: Animals; Cells, Cultured; Glucose; Glycolysis; Humans; Male; Mice, Inbred C57BL; T-Lymphocytes, Cytotoxic; Mice
PubMed: 34248978
DOI: 10.3389/fimmu.2021.689337 -
European Journal of Cancer (Oxford,... Feb 2024The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer... (Review)
Review
The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies.
Topics: Humans; CTLA-4 Antigen; T-Lymphocytes, Cytotoxic; Neoplasms; Italy; Immunotherapy
PubMed: 38169219
DOI: 10.1016/j.ejca.2023.113501 -
Journal For Immunotherapy of Cancer Oct 2020NF-κB is a key link between inflammation and cancer. Previous studies of NF-κB have largely focused on tumor cells, and the intrinsic function of NF-κB in T cells in...
BACKGROUND
NF-κB is a key link between inflammation and cancer. Previous studies of NF-κB have largely focused on tumor cells, and the intrinsic function of NF-κB in T cells in tumor development and response to immunotherapy is largely unknown. We aimed at testing the hypothesis that NF-κB1 (p50) activation in T cells underlies human colon cancer immune escape and human cancer non-response to anti-PD-1 immunotherapy.
METHODS
We screened NF-κB activation in human colon carcinoma and used mouse models to determine p50 function in tumor cells and immune cells. RNA-Seq was used to identify p50 target genes. p50 binding to target gene promoters were determined by electrophoresis mobility shift assay and chromatin immunoprecipitation. A p50 activation score was generated from gene expression profiling and used to link p50 activation to T-cell activation and function pre-nivolumab and post-nivolumab immunotherapy in human patients with cancer.
RESULTS
p50 is the dominant form of NF-κB that is highly activated in immune cells in the human colorectal carcinoma microenvironment and neighboring non-neoplastic colon epithelial cells. Tumor cell intrinsic p50 signaling and T-cell intrinsic p50 signaling exert opposing functions in tumor growth control in vivo. Deleting in tumor cells increased whereas in T cells decreased tumor growth in preclinical mouse models. Gene expression profiling identified as a p50 target in T cells. p50 binds directly to a previously uncharacterized κB sequence at the promoter in T cells, resulting in repression of expression in tumor-infiltrating cytotoxic T lymphocytes (CTLs) to induce a dysfunctional CTL phenotype to promote tumor immune escape. p50 activation is inversely correlated with both expression and T-cell tumor infiltration in human colorectal carcinoma. Furthermore, nivolumab immunotherapy decreased p50 activation and increased expression in human patients with melanoma.
CONCLUSIONS
Inflammation activates p50 that binds to the promoter to repress granzyme B expression in T cells, resulting in CTL dysfunction to confer tumor immune escape and decreased response to anti-PD-1 immunotherapy.
Topics: Animals; Disease Models, Animal; Female; Humans; Immunotherapy; Mice; T-Lymphocytes, Cytotoxic; Tumor Escape
PubMed: 33051343
DOI: 10.1136/jitc-2020-001365