Peripheral Th and NK cells are associated with response to lenvatinib plus PD-1 inhibitor in unresectable hepatocellular carcinoma.
Clinical immunology (Orlando, Fla.)
The value of peripheral blood lymphocyte subpopulations in predicting responses to lenvatinib combination with programmed death-1 (PD-1) inhibitors in unresectable hepatocellular carcinoma (HCC) was investigated. Fifteen patients received objective responses (OR) and sixteen patients had non-objective responses (NOR) were analyzed. The counts of peripheral blood lymphocyte subpopulations from patients were measured before treatment, second (at week 3), and third doses (at week 6) of the PD-1 inhibitor administration, and correlated with responses. Helper T (Th) cells and natural killers (NK) cells were more abundant in the OR group and found to be important predictors of OR in a stepwise multivariate logistic regression analysis. These cutoff values of Th and NK cells could help to distinguish OR from NOR cases accurately and provide clinical benefits.
10.1016/j.clim.2023.109290
Peripheral blood lymphocyte subpopulations as predictive biomarkers for first-line programmed death 1 inhibitors efficacy in esophageal squamous cell carcinoma: A retrospective study.
Medicine
Esophageal cancer (EC) poses a significant global health burden, necessitating effective treatment strategies. Immune checkpoint inhibitors have emerged as a promising therapeutic option for EC, but the identification of predictive biomarkers remains crucial for optimizing patient outcomes. We conducted a retrospective analysis of medical records from advanced esophageal squamous cell carcinoma patients treated with first-line programmed death 1 inhibitors. Peripheral blood lymphocyte subpopulations were evaluated using flow cytometry, while hematological tests provided data on neutrophil, lymphocyte, and monocyte counts. Cox regression and logistic regression analyses were employed to explore the association between lymphocyte subpopulations, baseline characteristics, and progression-free survival (PFS). Among the 100 initially included patients, 70 met eligibility criteria. Multivariate Cox regression analysis revealed a significant association between high CD16+CD56+ lymphocyte proportions and longer PFS, independent of other clinical variables. Similarly, a high CD4+/CD8+ ratio was correlated with prolonged PFS. Kaplan-Meier survival curves supported these findings. Logistic regression analysis indicated no significant differences in the CD4+/CD8+ ratio and CD16+CD56+ lymphocytes concerning baseline characteristics, suggesting their potential as independent prognostic markers. Our study highlights the predictive value of peripheral blood CD16+CD56+ lymphocytes and the CD4+/CD8+ ratio for the efficacy of programmed death 1 inhibitors in advanced esophageal squamous cell carcinoma patients. These findings underscore the importance of peripheral blood biomarkers in guiding personalized immunotherapy strategies and improving outcomes for EC patients.
10.1097/MD.0000000000039967
Peripheral Blood CD8 T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients.
International journal of molecular sciences
Peripheral blood CD8 T lymphocytes play a crucial role in cell-mediated immunity and tumor-related immune responses in breast cancer. In this study, label-free quantification analysis and gene set enrichment analysis (GSEA) of CD8 T lymphocytes in the peripheral blood of benign patients and patients with different breast cancer (BC) subtypes, i.e., luminal A, luminal B, and triple-negative breast cancer (TNBC), were performed using nano-UHPLC and Orbitrap mass spectrometry. Differential protein expression in CD8 T lymphocytes revealed significant downregulation (log FC ≥ 0.38 or ≤-0.38, adj. < 0.05), particularly in proteins involved in cytotoxicity, cytolysis, and proteolysis, such as granzymes (GZMs) and perforin 1 (PRF1). This downregulation was observed in the benign group (GZMH, GZMM, and PRF1) and luminal B (GZMA, GZMH) subtypes, whereas granzyme K (GZMK) was upregulated in TNBC in comparison to healthy controls. The RNA degradation pathway was significantly downregulated ( < 0.05, normalized enrichment score (NES) from -1.47 to -1.80) across all BC subtypes, suggesting a potential mechanism for regulating gene expression during T cell activation. Also, the Sm-like proteins (LSM2, LSM3, and LSM5) were significantly downregulated in the RNA degradation pathway. Proteomic analysis of CD8 T lymphocytes in peripheral blood across different breast cancer subtypes provides a comprehensive view of the molecular mechanisms of the systemic immune response that can significantly contribute to advancements in the diagnosis, treatment, and prognosis of this disease.
10.3390/ijms25126423
Phenotypic Characterization of B-Lymphocyte Subpopulations in Human Peripheral Blood: A Cost-Effective Seven-Color One-Tube Protocol.
Methods in molecular biology (Clifton, N.J.)
B cells are crucial components of the immune system, responsible for producing specific antibodies in response to infections and vaccines. Despite their uniform appearance, B cells display diverse surface molecules and functional properties, which are not yet fully understood. Apart from antibody production, B cells also play roles in antigen presentation and cytokine secretion, essential for initiating T-cell immune responses. Their significance as disease biomarkers and therapeutic targets has led to increased research focus. However, the lack of standardized protocols for B-cell identification and the variability in defining B-lymphocyte subpopulations pose some challenges. This paper proposes a B-cell identification panel throughout the evaluation of previous cytometry panels and nomenclature heterogeneity for B-cell subpopulations. Major subpopulations recognized in human peripheral blood include transitional, naive, switched memory, unswitched memory, double negative, and plasmablasts, characterized based on their functional and phenotypic features. We present a standardized flow cytometry protocol utilizing surface phenotypic markers (CD3, CD19, IgD, CD27, CD38, and CD24) to differentiate and analyze B-cell subpopulations. This practical and cost-effective panel can be used in various research and laboratory settings. The challenges of standardizing names and markers for classifying B-lymphocyte subpopulations are discussed, along with protocols utilizing multiple markers and gating strategies, allied with the importance of considering viability markers. In summary, this standardized protocol and panel provide a comprehensive approach to identifying B-cell subpopulations to enhance the reproducibility and comparability of B-cell subpopulation studies.
10.1007/978-1-0716-4128-6_3
CD4 Cytotoxic T cells - Phenotype, Function and Transcriptional Networks Controlling Their Differentiation Pathways.
Immunology letters
The two major subsets of peripheral T cells are classically divided into the CD4 T helper cells and the cytotoxic CD8 T cell lineage. However, the appearance of some effector CD4 T cell populations displaying cytotoxic activity, in particular during viral infections, has been observed, thus breaking the functional dichotomy of CD4 and CD8 T lymphocytes. The strong association of the appearance of CD4 cytotoxic T lymphocytes (CD4 CTLs) with viral infections suggests an important role of this subset in antiviral immunity by controlling viral replication and infection. Moreover, CD4 CTLs have been linked with anti-tumor activity and might also cause immunopathology in autoimmune diseases. This raises interest into the molecular mechanisms regulating CD4 CTL differentiation, which are poorly understood in comparison to differentiation pathways of other Th subsets. In this review, we provide a brief overview about key features of CD4 CTLs, including their role in viral infections and cancer immunity, and about the link between CD4 CTLs and immune-mediated diseases. Subsequently, we will discuss the current knowledge about transcriptional and epigenetic networks controlling CD4 CTL differentiation and highlight recent data suggesting a role for histone deacetylases in the generation of CD4 CTLs.
10.1016/j.imlet.2022.05.001
Natural killer cell homing and trafficking in tissues and tumors: from biology to application.
Signal transduction and targeted therapy
Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its "off-the-shelf" potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.
10.1038/s41392-022-01058-z
CD8 T Cell Exhaustion in Cancer.
Dolina Joseph S,Van Braeckel-Budimir Natalija,Thomas Graham D,Salek-Ardakani Shahram
Frontiers in immunology
A paradigm shift in the understanding of the exhausted CD8 T cell (T) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8 T is composed of multiple interconnected subpopulations. The heterogeneity within the CD8 T lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8 T. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8 T developmental continuum aimed at stabilizing functional subsets.
10.3389/fimmu.2021.715234
Clinical significance of peripheral blood and tumor tissue lymphocyte subsets in cervical cancer patients.
Wu Yutuan,Ye Shuang,Goswami Shyamal,Pei Xuan,Xiang Libing,Zhang Xiaoming,Yang Huijuan
BMC cancer
BACKGROUND:Alterations in peripheral blood lymphocytes in cervical cancer have been reported, although conflicting views exist. The present study investigated the distributions of lymphocyte subsets in tumor tissue and peripheral blood samples from cervical cancer patients and precancerous lesion patients, and evaluated the correlations of lymphocyte subsets with clinicopathological and prognostic variables. METHODS:A total of 44 patients with stage IB1-IIA2 cervical cancer and 13 precancerous lesion patients were included. Lymphocytes were collected from the tumor tissue and the peripheral blood, and isolated by Lymphoprep density gradient centrifugation. The percentages of lymphocyte subsets were quantified by flow cytometry analysis, and the differences between lymphocyte subsets in the tumor tissue and peripheral blood were compared by SPSS. In addition, the relationships between lymphocyte subsets and clinicopathological and prognostic variables were analyzed. RESULTS:Our results revealed that the amount of total T lymphocytes, CD8+ T cells, granulocytes, pDCs, CD16+ monocytes and CD56 NK cells were significantly higher in the tumor tissue than in the peripheral blood in the cervical cancer patients, while those of CD4+ T cells, CD4+/CD8+ cell ratio, rdT cells, BDCA1+ mDCs, total monocytes, CD14+ monocytes, NK cells and CD56 NK cells exhibited the opposite trend (p < 0.05). The levels of total pDCs and BDCA1+ mDCs in the peripheral blood were significantly lower in the cervical cancer patients than in the precancerous lesion patients, while the proportion of CD16+ monocytes was elevated (p < 0.05). In addition, some lymphocyte subsets, especially CD4+ cells and CD8+ cells, and the CD4+/CD8+ cell ratio were closely associated with clinicopathological and prognostic parameters. CONCLUSIONS:These results suggested that distinct alterations in infiltrating lymphocyte subsets occurred in the tumor and were associated with clinicopathological and prognostic parameters. Systemic impairment of the immune system may occur in the antitumor response of cervical cancer patients.
10.1186/s12885-020-6633-x
Tregs and Platelets Play Synergistic Roles in Tumor Immune Escape and Inflammatory Diseases.
Critical reviews in immunology
Regulatory T cells (Tregs), a fraction of CD4+ T cells with immunosuppressive characteristics, are strongly linked to a number of inflammatory and autoimmune disorders. Furthermore, it also contributes to the development of tumors. Tregs infiltrate into the tumor microenvironment (TME), dampen the anti-tumor immune reaction, and facilitate tumoral immune escape. Besides the well-known hemostatic roles, mounting evidence indicates that platelets may also function as immune cells and engage in cancer immune escape. In addition, substantial evidence shows that platelets or platelet-derived mediators can regulate the proliferation, differentiation, and functions of many immune cells. Platelets also play important roles in promoting tumor cell proliferation and helping tumor cells evade immune surveillance. Here we summarize the regulatory effects of platelets in Treg proliferation, differentiation and functions and highlight the potential synergistic roles of platelets and Tregs in tumor cell immune escape.
10.1615/CritRevImmunol.2023047234
Polysaccharides regulate Th1/Th2 balance: A new strategy for tumor immunotherapy.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
T helper (Th) cells have received extensive attention owing to their indispensable roles in anti-tumor immune responses. Th1 and Th2 cells are two key subsets of Th cells that exist in relative equilibrium through the secretion of cytokines that suppress their respective immune response. When the type of cytokine in the tumor microenvironment is altered, this equilibrium may be disrupted, leading to a shift from Th1 to Th2 immune response. Th1/Th2 imbalance is one of the decisive factors in the development of malignant tumors. Therefore, focusing on the balance of Th1/Th2 anti-tumor immune responses may enable future breakthroughs in cancer immunotherapy. Polysaccharides can regulate the imbalance between Th1 and Th2 cells and their characteristic cytokine profiles, thereby improving the tumor immune microenvironment. To our knowledge, this study is the most comprehensive assessment of the regulation of the tumor Th1/Th2 balance by polysaccharides. Herein, we systematically summarized the intrinsic molecular mechanisms of polysaccharides in the regulation of Th1 and Th2 cells to provide a new perspective and potential target drugs for improved anti-tumor immunity and delayed tumor progression.
10.1016/j.biopha.2023.115976
B cell heterogeneity, plasticity, and functional diversity in cancer microenvironments.
Oncogene
B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.
10.1038/s41388-021-01918-y
Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer.
Frontiers in immunology
In immune system, B cells are classically positive modulators that regulate inflammation and immune responses. Regulatory B cells (Bregs) are a subset of B cells which play crucial roles in various conditions, including infection, allergies, autoimmune diseases, transplantation, and tumors. Until now, unequivocal surface markers for Bregs still lack consensus, although numerous Breg subsets have been identified. Generally, Bregs exert their immunoregulatory functions mainly through cytokine secretion and intercellular contact. In the tumor microenvironment, Bregs suppress effector T cells, induce regulatory T cells and target other tumor-infiltrating immune cells, such as myeloid-derived suppressor cells, natural killer cells and macrophages, to hamper anti-tumor immunity. Meanwhile, the cross-regulations between Bregs and tumor cells often result in tumor escape from immunosurveillance. In addition, accumulating evidence suggests that Bregs are closely associated with many clinicopathological factors of cancer patients and might be potential biomarkers for accessing patient survival. Thus, Bregs are potential therapeutic targets for future immunotherapy in cancer patients. In this review, we will discuss the phenotypes, functions, and clinical relevance of Bregs in cancer.
10.3389/fimmu.2020.582657
T Cell Memory in Infection, Cancer, and Autoimmunity.
Frontiers in immunology
Long-term immunological memory represents a unique performance of the adaptive immunity selected during evolution to support long-term survival of species in vertebrates, through protection against dangerous "invaders", namely, infectious agents or unwanted (e.g., tumor) cells. The balance between the development of T cell memory and various mechanisms of immunoregulation (namely, T cell effector exhaustion and regulatory T cell suppression) dictates the fate in providing protection or not in different conditions, such as (acute or chronic) infection, vaccination, cancer, and autoimmunity. Here, these different environments are taken in consideration to outline the up-to-date cellular and molecular features regulating the development or damping of immunological memory and to delineate therapeutic strategies capable to improve or control it, in order to address pathological contexts, such as infection, tumor, and autoimmunity.
10.3389/fimmu.2021.811968
Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies.
Frontiers in immunology
The clinical success of cancer immunotherapies targeting PD-1 and CTLA-4 has ignited a substantial research effort to improve our understanding of tumor immunity. Recent studies have revealed that the immune contexture of a tumor influences therapeutic response and survival benefit for cancer patients. Identifying treatment modalities that limit immunosuppression, relieve T cell exhaustion, and potentiate effector functions in the tumor microenvironment (TME) is of much interest. In particular, combinatorial therapeutic approaches that re-educate the TME by limiting the accumulation of immunosuppressive immune cells, such as Foxp3 regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), while promoting CD8 and CD4 effector T cell activity is critical. Here, we review key approaches to target these immunosuppressive immune cell subsets and signaling molecules and define the impact of these changes to the tumor milieu. We will highlight the preclinical and clinical evidence for their ability to improve anti-tumor immune responses as well as strategies and challenges for their implementation. Together, this review will provide understanding of therapeutic approaches to efficiently shape the TME and reinvigorate the immune response against cancer.
10.3389/fimmu.2020.01633
The role of ILC subsets in cancer.
Seminars in immunology
The family of innate lymphoid cells (ILCs) are composed of five canonical subsets, NK cells, ILC1, ILC2, ILC3 and Lymphoid tissue inducer cells. ILCs have important functions in early stages of immune response towards infectious agents. ILCs are highly plastic enabling rapid modification of their functions dependent on the type of microbe and tissue environment to optimally counter these microbes. Data that still accumulate in a rapid pace indicate that these cells are also involved in immunity against tumor cells. Paradoxically ILC subsets have been shown to have tumor suppressing and tumor promoting activities. In this brief review we provide a snapshot of our current knowledge of characteristics and functions of tumor infiltrating ILC subsets and speculate on how these cells can be harnessed to mediate anti-tumor immunity.
10.1016/j.smim.2022.101654
Why Treg should be the focus of cancer immunotherapy: The latest thought.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in the immune system. What's more, regulatory T cells often play an immunosuppressive role, which mainly plays a role in maintaining the stability of the immune system and regulating the immune response in the body. However, recent studies have shown that not only playing a role in autoimmune diseases, organ transplantation, and other aspects, regulatory T cells can also play a role in the immune escape of tumors in the body, through various mechanisms to help tumor cells escape from the demic immune system, weakening the anti-cancer effect in the body. For a better understanding of the role that regulatory T cells can play in cancer, and to be able to use regulatory T cells for tumor immunotherapy more quickly. This review focuses on the research progress of various mechanisms of regulatory T cells in the tumor environment, the related research of tumor cells acting on regulatory T cells, and the existing various therapeutic methods acting on regulatory T cells.
10.1016/j.biopha.2023.115142
KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.
Journal for immunotherapy of cancer
Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a HeliosKLRG1 subset of tumor-infiltrating regulatory T cells was associated with tumor progression from immune equilibrium to escape and was also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumor-infiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1 CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker discovery.
10.1136/jitc-2023-006782
Features and roles of T helper 22 cells in immunological diseases and malignancies.
Scandinavian journal of immunology
T helper 22 (Th22) cell populations are a newly identified subset of CD4 T cells that primarily mediate biological effects on the epithelial barrier through interleukin (IL)-22. Although, new studies showed that both Th22 and IL-22 are closely associated with the pathogenesis of inflammatory, autoimmune and allergic disease as well as malignancies. In this review, we aim to describe the development and characteristics of Th22 cells as well as their roles in the immunopathogenesis of immune-related disorders and cancer.
10.1111/sji.13030
High-dimensional single-cell analysis of human natural killer cell heterogeneity.
Nature immunology
Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.
10.1038/s41590-024-01883-0
Single-cell profiling of tumor-infiltrating TCF1/TCF7 T cells reveals a T lymphocyte subset associated with tertiary lymphoid structures/organs and a superior prognosis in oral cancer.
Peng Yu,Xiao Liping,Rong Haixu,Ou Zhanpeng,Cai Tingting,Liu Niu,Li Bowen,Zhang Lizao,Wu Fan,Lan Tianjun,Lin Xinyu,Li Qunxing,Ren Siqi,Fan Song,Li Jinsong
Oral oncology
OBJECTIVES:Despite substantial advances in treatment, clinical outcomes for oral squamous cell carcinoma (OSCC) remain unsatisfactory. Tumor-infiltrating lymphocytes (TILs) are an important prognostic factor for patients and are heterogeneous. Some studies have suggested that TCF1/TCF7 T cells and tertiary lymphatic structure/organ (TLS) play an important role in tumor immunity. However, how they affect tumor immunity and whether they are related to prognosis in OSCC have not been reported in detail. MATERIALS AND METHODS:We isolated OSCC cells and performed single-cell RNA sequencing (scRNA-seq). We used immunohistochemistry (IHC) to analyze the relationship between TLSs and prognosis. Multiplex immunohistochemistry (MIHC), flow cytometry (FCM) and spatial analysis were performed to verify the characteristics of TCF1/TCF7 T cells. The prognostic significance and upstream regulatory network of the TCF1/TCF7 T cell subpopulation were determined by multivariate analysis and Scenic software. RESULTS:We found a strong association between TCF1/TCF7 T cell subsets, TLSs and prognosis. The results suggested that TCF1/TCF7 T cells express high levels of TLS-related genes and low levels of immune checkpoint molecules. Finally, we found that TCF1/TCF7 T cells were significantly associated with favorable outcomes. We also describe the upstream drivers that these cells rely on. CONCLUSIONS:TCF1/TCF7 T cells could be used as a new therapeutic target to regulate the immune response of OSCC and are expected to be a new prognostic marker.
10.1016/j.oraloncology.2021.105348
Extricating human tumour immune alterations from tissue inflammation.
Nature
Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (T) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1 T cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1 T cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.
10.1038/s41586-022-04718-w
T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.
Frontiers in immunology
Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.
10.3389/fimmu.2021.761448
Differentiation and Regulation of T Cells: A Balancing Act for Cancer Immunotherapy.
Basu Amrita,Ramamoorthi Ganesan,Albert Gabriella,Gallen Corey,Beyer Amber,Snyder Colin,Koski Gary,Disis Mary L,Czerniecki Brian J,Kodumudi Krithika
Frontiers in immunology
Current success of immunotherapy in cancer has drawn attention to the subsets of T cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic T subsets in the tumor milieu further contributes to the complexity of regulation of T cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of T cells, with an emphasis on regulation of different T cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4 T1 cells and subsequent priming of CD8 cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic T2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory T9 and T cells, immunosuppressive T cells, and the duality of T17 function contribute to tip the balance of anti- vs pro-tumorigenic T responses in the tumor. We highlight the developing knowledge of CD4 T1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4 T1 immunity, and how opposing action of T cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4 T cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic T subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.
10.3389/fimmu.2021.669474
A cross-talk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity.
Boulch Morgane,Cazaux Marine,Loe-Mie Yann,Thibaut Ronan,Corre Béatrice,Lemaître Fabrice,Grandjean Capucine L,Garcia Zacarias,Bousso Philippe
Science immunology
Chimeric antigen receptor (CAR) T cell therapy relies on the activity of a large pool of tumor-targeting cytotoxic effectors. Whether CAR T cells act autonomously or require interactions with the tumor microenvironment (TME) remains incompletely understood. Here, we report an essential cross-talk between CAR T cell subsets and the TME for tumor control in an immunocompetent mouse B cell lymphoma model of anti-CD19 CAR T cell therapy. Using single-cell RNA sequencing, we revealed substantial modification of the TME during CAR T cell therapy. Interferon-γ (IFN-γ) produced by CAR T cells not only enhanced endogenous T and natural killer cell activity but was also essential for sustaining CAR T cell cytotoxicity, as revealed by intravital imaging. CAR T cell-derived IFN-γ facilitated host interleukin-12 production that supported host immune and CAR T cell responses. Compared with CD8 CAR T cells, CD4 CAR T cells were more efficient at host immune activation but less capable of direct tumor killing. In summary, CAR T cells do not act independently in vivo but rely instead on cytokine-mediated cross-talk with the TME for optimal activity. Invigorating CAR T cell interplay with the host represents an attractive strategy to prevent relapses after therapy.
10.1126/sciimmunol.abd4344
CD8 T cell states in human cancer: insights from single-cell analysis.
van der Leun Anne M,Thommen Daniela S,Schumacher Ton N
Nature reviews. Cancer
The T cell infiltrates that are formed in human cancers are a modifier of natural disease progression and also determine the probability of clinical response to cancer immunotherapies. Recent technological advances that allow the single-cell analysis of phenotypic and transcriptional states have revealed a vast heterogeneity of intratumoural T cell states, both within and between patients, and the observation of this heterogeneity makes it critical to understand the relationship between individual T cell states and therapy response. This Review covers our current knowledge of the T cell states that are present in human tumours and the role that different T cell populations have been hypothesized to play within the tumour microenvironment, with a particular focus on CD8 T cells. The three key models that are discussed herein are as follows: (1) the dysfunction of T cells in human cancer is associated with a change in T cell functionality rather than inactivity; (2) antigen recognition in the tumour microenvironment is an important driver of T cell dysfunctionality and the presence of dysfunctional T cells can hence be used as a proxy for the presence of a tumour-reactive T cell compartment; (3) a less dysfunctional population of tumour-reactive T cells may be required to drive a durable response to T cell immune checkpoint blockade.
10.1038/s41568-019-0235-4
Precursor exhausted T cells: key to successful immunotherapy?
Kallies Axel,Zehn Dietmar,Utzschneider Daniel T
Nature reviews. Immunology
Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8 T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, which we refer to as 'precursor exhausted' T (T) cells, are responsible for the proliferative burst that generates effector T cells in response to immune checkpoint blockade targeting programmed cell death 1 (PD1), and increased T cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of T cells not only represents a paradigm shift in our understanding of the mechanisms that maintain CD8 T cell responses in chronic infections and tumours but also opens up unexpected avenues for the development of new and innovative therapeutic approaches. In this Opinion article, we discuss the differentiation and function of T cells and suggest that targeting these cells may be key for successful immunotherapy.
10.1038/s41577-019-0223-7
Pan-cancer single-cell landscape of tumor-infiltrating T cells.
Science (New York, N.Y.)
T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8 T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.
10.1126/science.abe6474
Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects.
Molecular cancer
Regulatory T cells (Tregs) characterized by the expression of the master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance of tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot in the field. However, Tregs are also essential for the maintenance of the immune tolerance of the body and share many molecular signalling pathways with conventional T cells, including cytotoxic T cells, the primary mediators of tumour immunity. Hence, the inability to specifically target and neutralize Tregs in the tumour microenvironment without globally compromising self-tolerance poses a significant challenge. Here, we review recent advances in characterizing tumour-infiltrating Tregs with a focus on the functional roles of costimulatory and inhibitory receptors in Tregs, evaluate their potential as clinical targets, and systematically summarize their roles in potential treatment strategies. Also, we propose modalities to integrate our increasing knowledge on Tregs phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Finally, we propose possible treatment strategies that can be used to develop Treg-targeted therapies.
10.1186/s12943-020-01234-1