• Cancer immunotherapy
• Immune checkpoint blockade
• Immune normalization
• Tumor immune evasion

• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplasms/drug therapy
• Immunotherapy/methods
• Animals

• 2022YFE0102100 the National Key Research and Development Program of China
• U22A20307 and 81930041 the National Natural Science Foundation of China

• Cancer immunotherapy
• Ferroptosis
• Nanoparticles
• Nanozyme
• Photothermal therapy
• Prussian blue

• Ferrocyanides/chemistry
• Humans
• Immunotherapy/methods
• Neoplasms/therapy
• Neoplasms/immunology
• Nanoparticles/chemistry
• Tumor Microenvironment/drug effects
• Animals

• 82304393 National Natural Science Foundation
• QML20231601 Beijing Municipal Administration of Hospitals' Youth Programme
• KJ2024CX024 Tongzhou District Health Development Research Reserve Project Foundation
• PX2021061 Beijing Municipal Administration of Hospitals' Incubating Programme
• Beijing Municipal Administration of Hospitals’ Youth Programme
• Beijing Municipal Administration of Hospitals’ Incubating Programme

• Humans
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Protein Kinase Inhibitors/pharmacokinetics
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Protein Serine-Threonine Kinases/metabolism
• Drug Discovery
• Structure-Activity Relationship
• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology
• Neoplasms/drug therapy
• Molecular Structure

• chemotherapy
• gastric cancer
• gastroesophageal junction carcinoma
• meta-analysis
• pembrolizumab

• T cell responses
• cancer immunotherapy
• interferon γ
• trained immunity
• tumor microenvironment

• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Immunotherapy/methods
• Tumor Microenvironment/immunology
• Animals
• Immunity, Innate
• Immunologic Memory
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• T-Lymphocytes/immunology
• Interferon-gamma/metabolism
• Interferon-gamma/immunology
• Trained Immunity

• bone
• exosome
• programmed death-ligand 1
• sarcoma
• soft tissue

• Colorectal cancer
• Magnetic lipid nanoparticle
• Microbiota metabolite regulation
• Oral administration
• Synergistic therapy

• Mice
• Animals
• Colorectal Neoplasms/drug therapy
• Nanoparticles/therapeutic use
• Gastrointestinal Microbiome
• Administration, Oral
• Magnetic Phenomena
• Tumor Microenvironment
• Liposomes

• Triple Negative Breast Neoplasms/therapy
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/immunology
• Photochemotherapy
• Humans
• Apoptosis/drug effects
• Immunotherapy
• Photosensitizing Agents/pharmacology
• Photosensitizing Agents/chemistry
• Photosensitizing Agents/administration & dosage
• Female
• Reactive Oxygen Species/metabolism
• Animals
• Mice
• Biphenyl Compounds/pharmacology
• Biphenyl Compounds/chemistry
• Sulfonamides/pharmacology
• Sulfonamides/chemistry
• Chlorophyllides
• Cell Line, Tumor
• Piperazines/pharmacology
• Piperazines/chemistry
• Nitrophenols/pharmacology
• Nitrophenols/chemistry
• Nanoparticles/chemistry
• Porphyrins/pharmacology
• Porphyrins/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry

• PD‐L1
• ferritin
• immunotherapy
• multivalent nanobody

• Animals
• Humans
• Mice
• B7-H1 Antigen/immunology
• B7-H1 Antigen/antagonists & inhibitors
• Cell Line, Tumor
• Disease Models, Animal
• Ferritins/immunology
• Immunotherapy/methods
• Indocyanine Green
• Neoplasms/therapy
• Neoplasms/immunology
• Single-Domain Antibodies/immunology
• Single-Domain Antibodies/pharmacology

• 2020YFA0710700 National Key R&D Program of China
• 202303a07020004 Plans for Major Provincial Science & Technology Projects
• 52021002 National Natural Science Foundation of China
• 22177109 National Natural Science Foundation of China
• 22377116 National Natural Science Foundation of China
• National Key R&D Program of China
• National Natural Science Foundation of China

• Bibliometric analysis
• Bispecific T-cell engager
• Bispecific antibodies
• Cancer immunotherapy
• Data visualization
• Research hotspots

• Advanced gastric adenocarcinoma
• neoadjuvant chemotherapy plus programmed death 1 antibody (neoadjuvant chemotherapy plus PD-1 antibody)
• nomogram
• pathological complete response (pCR)

• Galectin-1
• angiogenesis
• immune modulation
• pancreatic ductal adenocarcinoma
• tumor microenvironment

• Humans
• Carcinoma, Pancreatic Ductal/drug therapy
• Galectin 1/genetics
• Galectin 1/metabolism
• Immune Evasion
• Pancreatic Neoplasms/drug therapy
• Tumor Microenvironment

• JP15/19 Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia

• carcinoembryonic antigen (cea)
• colorectal cancer
• intermittent fasting
• lactate dehydrogenase (ldh)
• tumor biomarkers

• Chemodynamic therapy
• cGAS-STING
• immunogenic cell death
• photothermal therapy
• reactive oxygen species

• Cell Line, Tumor
• Cytokines
• Humans
• Immunogenic Cell Death
• Immunotherapy
• Manganese
• Manganese Compounds
• Melanoma/drug therapy
• Micelles
• Nanoparticles/chemistry
• Neoplasms/therapy
• Nucleotidyltransferases
• Polyethylene Glycols/chemistry
• Polymers
• Reactive Oxygen Species/metabolism
• Sulfides
• Tumor Microenvironment
• Zinc
• Zinc Compounds

Breast cancer and gynecological tumors seriously endanger women’s physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

• Cancer therapy
• Dendritic cells
• Immune response
• Nanodrug
• Nanoparticle

• Amorphous iron oxide nanoparticle
• Immunotherapy
• Interventional photothermal therapy
• Magnetic resonance temperature imaging
• Pancreatic cancer

• Animals
• Cell Line, Tumor
• Ferric Compounds
• Immunotherapy
• Indocyanine Green
• Mice
• Nanoparticles
• Pancreatic Neoplasms/therapy
• Phototherapy
• Photothermal Therapy
• Tumor Microenvironment

• R01 CA205348 NCI NIH HHS
• S10 OD023508 NIH HHS

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells.

The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3).

The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis.

In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation.

• Cancer immunotherapy
• Cholesterolized liposomes
• Lymph nodes
• TLR7 agonist

Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1–deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1–deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K–AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1–deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.

• NK-92
• adoptive cell transfer
• antitumor immunity
• programmed cell death protein 1
• programmed death-ligand 1
• tumor microenvironment

• immunotherapy
• programmed death 1/programmed death ligand 1
• immune checkpoint inhibitors
• non-small cell lung cancer

• Angiogenesis Inhibitors/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Humans
• Immunotherapy
• Lung Neoplasms/drug therapy
• Protein Kinase Inhibitors/therapeutic use

Although rare, malignant bone sarcomas have devastating clinical implications for the health and survival of young adults and children. To date, efforts to identify the molecular drivers and targets have focused on cancer cells or on the interplay between cancer cells and stromal cells in the tumour microenvironment. On the contrary, in the current literature, the role of the chemical-physical conditions of the tumour microenvironment that may be implicated in sarcoma aggressiveness and progression are poorly reported and discussed. Among these, extracellular acidosis is a well-recognized hallmark of bone sarcomas and promotes cancer growth and dissemination but data presented on this topic are fragmented. Hence, we intended to provide a general and comprehensive overview of the causes and implications of acidosis in bone sarcoma.

In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated.

• acid-sensing ion channels
• acridine orange
• bone sarcoma
• carbonic anhydrase IX
• extracellular acidosis
• tumour microenvironment
• tumour-associated stroma
• vacuolar-ATP-ase

Colorectal cancer (CRC) has a global burden of disease. Our current understanding of CRC has progressed from initial discoveries which focused on the stepwise accumulation of key driver mutations, as encapsulated in the Vogelstein model, to one in which marked heterogeneity leads to a complex interplay between clonal populations. Current evidence suggests that an initial explosion, or “Big Bang”, of genetic diversity is followed by a period of neutral dynamics. A thorough understanding of this interplay between clonal populations during neutral evolution gives insights into the roles in which driver genes may participate in the progress from normal colonic epithelium to adenoma and carcinoma. Recent advances have focused not only on genetics, transcriptomics, and proteomics but have also investigated the ecological and evolutionary processes which transform normal cells into cancer. This review first describes the role which driver mutations play in the Vogelstein model and subsequently demonstrates the evidence which supports a more complex model. This article also aims to underscore the significance of tumour heterogeneity and diverse clonal populations in cancer progression.

The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%–30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003).

To determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003, in vitro luciferase reporter and primary cell assays were used to test the potency of programmed cell death 1 ligand 1 (PD-L1) blockade and PD-L1-mediated 4-1BB activation via cross-bridging. X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms, and accurate binding kinetics were determined using standard affinity measurement techniques. Human 4-1BB and/or PD-L1 knock-in mice were used in cancer models for testing the in vivo antitumor efficacy of PM1003, and safety was evaluated further.

PM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation in vivo.

A unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1 in vitro. Antitumor activity with minimal toxicity was found in vivo. Thus, PM1003 is a uniquely differentiating and next generation therapeutic agent for cancer therapy.

• antibody specificity
• antigens
• differentiation
• tumor microenvironment

Pancreatic cancer, a highly lethal cancer, has the lowest 5-year survival rate for several reasons, including its tendency for the late diagnosis, a lack of serologic markers for screening, aggressive local invasion, its early metastatic dissemination, and its resistance to chemotherapy/radiotherapy. Pancreatic cancer evades immunologic elimination by a variety of mechanisms, including induction of an immunosuppressive microenvironment. Cancer-associated fibroblasts interact with inhibitory immune cells, such as tumor-associated macrophages and regulatory T cells, to form an inflammatory shell-like desmoplastic stroma around tumor cells. Immunotherapy has the potential to mobilize the immune system to eliminate cancer cells. Nevertheless, although immunotherapy has shown brilliant results across a wide range of malignancies, only anti-programmed cell death 1 antibodies have been approved for use in patients with pancreatic cancer who test positive for microsatellite instability or mismatch repair deficiency. Some patients treated with immunotherapy who show progression based on conventional response criteria may prove to have a durable response later. Continuation of immune-based treatment beyond disease progression can be chosen if the patient is clinically stable. Immunotherapeutic approaches for pancreatic cancer treatment deserve further exploration, given the plethora of combination trials with other immunotherapeutic agents, targeted therapy, stroma-modulating agents, chemotherapy, and multi-way combination therapies.

• Pancreatic adenocarcinoma
• Pancreatic cancer
• Immunotherapy
• Immune checkpoint inhibitor

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.

• CAR
• CD8 T cells
• cancer
• checkpoint inhibitor
• cytotoxic T lymphocytes
• immunotherapy
• tumour antigen

In this study we evaluated the potential of expanded NK cells (eNKs) from two sources combined with the mAbs daratumumab and pembrolizumab to target primary multiple myeloma (MM) cells ex vivo. In order to ascertain the best source of NK cells, we expanded and activated NK cells from peripheral blood (PB) of healthy adult donors and from umbilical cord blood (UCB). The resulting expanded NK (eNK) cells express CD16, necessary for carrying out antibody-dependent cellular cytotoxicity (ADCC). Cytotoxicity assays were performed on bone marrow aspirates of 18 MM patients and 4 patients with monoclonal gammopathy of undetermined significance (MGUS). Expression levels of PD-1 on eNKs and PD-L1 on MM and MGUS cells were also quantified. Results indicate that most eNKs obtained using our expansion protocol express a low percentage of PD-1⁺ cells. UCB eNKs were highly cytotoxic against MM cells and addition of daratumumab or pembrolizumab did not further increase their cytotoxicity. PB eNKs, while effective against MM cells, were significantly more cytotoxic when combined with daratumumab. In a minority of cases, eNK cells showed a detectable population of PD1⁺ cells. This correlated with low cytotoxic activity, particularly in UCB eNKs. Addition of pembrolizumab did not restore their activity. Results indicate that UCB eNKs are to be preferentially used against MM in the absence of daratumumab while PB eNKs have significant cytotoxic advantage when combined with this mAb.

• Multiple Myeloma
• NK cells
• PD-1
• cell Therapy and Immunotherapy
• cytotoxicity
• daratumumab

• immune checkpoint
• sarcoma
• tumor-infiltrating immune cells

• Biomarkers, Tumor/genetics
• Carrier Proteins/genetics
• Computational Biology
• Female
• GTP Phosphohydrolases/genetics
• GTP-Binding Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Histocompatibility Antigens Class I/genetics
• Humans
• LIM Domain Proteins/genetics
• Liver X Receptors/genetics
• Male
• Membrane Proteins/genetics
• Mutation
• Prognosis
• R-SNARE Proteins/genetics
• Sarcoma/genetics
• Sarcoma/immunology
• Sarcoma/mortality
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology
• HLA-E Antigens

• Anti-programmed cell death ligand 1
• Consolidation therapy
• Durvalumab
• Immune checkpoint inhibitors
• Immunotherapy
• Non-small cell lung cancer
• PACIFIC
• Unresectable stage III lung cancer

• cancer
• checkpoint inhibitors
• immunotherapy
• innate immunity
• melanoma
• myeloid cells
• nanobiologics
• nanomedicine
• nanotechnology
• trained immunity

• Acetylmuramyl-Alanyl-Isoglutamine/metabolism
• Animals
• Behavior, Animal
• Bone Marrow Cells/drug effects
• Bone Marrow Cells/metabolism
• Cell Proliferation/drug effects
• Cholesterol/metabolism
• Female
• Hematopoietic Stem Cells/drug effects
• Hematopoietic Stem Cells/metabolism
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Immunity/drug effects
• Immunotherapy
• Lipoproteins, HDL/metabolism
• Melanoma, Experimental/drug therapy
• Melanoma, Experimental/pathology
• Mice, Inbred C57BL
• Nanotechnology
• Primates
• Tissue Distribution/drug effects
• Tumor Microenvironment/drug effects

• R01 CA244780 NCI NIH HHS
• R01 HL144072 NHLBI NIH HHS
• F32 CA247414 NCI NIH HHS
• P01 HL131478 NHLBI NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 AI139623 NIAID NIH HHS
• R01 HL143814 NHLBI NIH HHS
• R01 DA049547 NIDA NIH HHS
• R01 CA220234 NCI NIH HHS
• P30 CA196521 NCI NIH HHS
• K22 CA226040 NCI NIH HHS
• T32 CA078207 NCI NIH HHS
• K22 CA196750 NCI NIH HHS

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors have been shown to significantly prolong the overall survival (OS) in a wide range of cancers. However, its application in clear cell renal cell carcinoma (ccRCC) is limited due to the therapy response, and the prognostic value of CTLA4 in ccRCC has not been investigated in detail.

By using immunohistochemistry, Kaplan–Meier (K–M) analysis, uni- and multi-variate Cox analysis, we comprehensively and systematically studied the prognostic value of CTLA4 in ccRCC. Then, we applied Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and CIBERSORT, ESTIMATE algorithm, ssGSEA and somatic mutation analyses to reveal the impact of CTLA4 on the landscape of tumor-infiltrating lymphocytes (TILs) infiltration and genetic mutation. Besides, given current concerns caused by combined immunotherapy, we also investigated the relationship between CTLA4 and other immune checkpoints.

In vitro experiment and data mining showed that, CTLA4 was up-regulated in ccRCC tissues and closely related to the disease progression as well as a poor prognosis. Deeper researches demonstrated that CTLA4 regulates T cell activation and was significantly linked to TIL-abundant tumor microenvironment (TME), but was accompanied by an immunosuppressed phenotype. Mutation analysis showed that CTLA4 was associated with more frequent BRCA-associated protein 1 (BAP1) mutation. Moreover, we found that CTLA4 was markedly correlated with multiple immune checkpoints, which suggested that ccRCC patients with high expressed CTLA4 may benefit more from immune checkpoint blockades (ICBs) combined therapy.

CTLA4 has a profound impact on the landscape of TILs and genetic mutation, and can be used as the biomarker with high prognosis value in ccRCC.

• CD8+ T cells
• CTLA4
• Clear cell renal cell carcinoma
• Immune checkpoints
• Prognosis
• Tumor microenvironment
• Tumor-infiltrating lymphocytes

Chronic lymphocytic leukemia (CLL) is characterized by the peripheral accumulation of neoplastic B cells and is frequently complicated by the systemic immunosuppression associated with an impairment in B and T lymphocyte activation. We hypothesized that the expression of immune checkpoint suppressors B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen (CTLA-4) is disturbed in both lymphocyte subpopulations in CLL. The expression of CTLA-4 and BTLA mRNA was determined by real-time PCR, while CTLA-4 protein expression (surface or intracellular) was estimated in BTLA+ lymphocytes by flow cytometry. In CLL patients, we observed a higher gene transcript level of BTLA and CTLA-4 than in healthy individuals in both freshly isolated and PMA stimulated B and T cells. Remarkably, lower amounts of both inhibitory proteins were found in peripheral blood (PB) CLL B cells, whereas normal BTLA and elevated CTLA-4 were found in T cells. Consistently, there was a prevalence of CTLA-4+ cells within circulating BTLA+ T cells cells of patients confronting PB healthy cells. After in vitro stimulation, the only change found in CLL patients was a decrease in BTLA expression in B and T lymphocytes. In contrast, healthy lymphocytes responded more vigorously as regards the BTLA and CTLA expression with substantially higher frequency of CD69+ cells under the stimulating condition compared to corresponding cells from the CLL group. Our results indicate that CLL development is associated with the affected expression of BTLA and CTLA-4 checkpoint receptors in PB and its impaired expression might be associated with lowering of the threshold for B cell activation and proliferation, while upregulated CTLA-4 expression in CLL peripheral BTLA+ T cells may contribute to suppressed T cell effector functions. This hypothesis needs to be validated in future studies, which would allow us to explain how the increased or decreased expression of these molecules affects the cell function.