Figure 2 - uploaded by Luca Simula
Content may be subject to copyright.
Proposed models of PD-1 engagement on T-cell migration in tumor islets and in the stroma. Top: in tumor islets, PD-1 engagement reduces the stop signal and leads to the disengagement of T cells from cancer cells. Bottom: in the surrounding stroma, PD-1 engagement reduces T-cell migration by altering signaling pathways triggered by chemokine receptors. Figure created with BioRender.
Source publication
Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remi...
Contexts in source publication
Context 1
... reasons can explain these contradictory findings. First, the motility of T cells in response to ICI may differ depending on their spatial localization ( Figure 2). In tumor islets where T cells are in contact with cancer cells, PD-1 and CTLA-4 likely act by interrupting TCR-mediated stop signals. ...
Context 2
... impact of PD-1 or CTLA-4 engagement on T-cell motility in the absence of TCR-induced signals is not known for the moment. It is possible that by reducing the signals triggered by chemokine receptors, immune checkpoint proteins mediate inhibitory effects on T-cell migration as opposed to the T-APC disengagement ( Figure 2). In such a setting, ICI treatment would increase T-cell trafficking in the stroma and decrease it in the tumor islets. ...
Context 3
... reasons can explain these contradictory findings. First, the motility of T cells in response to ICI may differ depending on their spatial localization (Figure 2). In tumor islets where T cells are in contact with cancer cells, PD-1 and CTLA-4 likely act by interrupting TCR-mediated stop signals. ...
Context 4
... impact of PD-1 or CTLA-4 engagement on T-cell motility in the absence of TCR-induced signals is not known for the moment. It is possible that by reducing the signals triggered by chemokine receptors, immune checkpoint proteins mediate inhibitory effects on T-cell migration as opposed to the T-APC disengagement (Figure 2). In such a setting, ICI treatment would increase T-cell trafficking in the stroma and decrease it in the tumor islets. ...
Similar publications
Glioblastoma (GBM), one of the most lethal brain cancers in adults, accounts for 48.6% of all malignant primary CNS tumors diagnosed each year. The 5-year survival rate of GBM patients remains less than 10% even after they receive the standard-of-care treatment, including maximal safe resection, adjuvant radiation, and chemotherapy with temozolomid...
Citations
... Immunosuppressive TME [8,129,[146][147][148][149][150][151][152][153][154][155][156][157][158] CAR-T cells can release cytokines or antibodies inducing antibody-dependent cell-mediated cytotoxicity [149,[159][160][161]. [156,[162][163][164][165][166][167]. Elimination of co-inhibiting molecules [138,156,159,[168][169][170][171][172]. ...
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard treatments including surgical resection, radiotherapy, and chemotherapy, have failed to significantly improve the prognosis of glioblastoma patients. Currently, immunotherapeutic approaches based on vaccines, chimeric antigen-receptor T-cells, checkpoint inhibitors, and oncolytic virotherapy are showing promising results in clinical trials. The combination of different immunotherapeutic approaches is proving satisfactory and promising. In view of the challenges of immunotherapy and the resistance of glioblastomas, the treatment of these tumors requires further efforts. In this review, we explore the obstacles that potentially influence the efficacy of the response to immunotherapy and that should be taken into account in clinical trials. This article provides a comprehensive review of vaccine therapy for glioblastoma. In addition, we identify the main biomarkers, including isocitrate dehydrogenase, epidermal growth factor receptor, and telomerase reverse transcriptase, known as potential immunotherapeutic targets in glioblastoma, as well as the current status of clinical trials. This paper also lists proposed solutions to overcome the obstacles facing immunotherapy in glioblastomas.
... However, the application of CAR-T cell therapy for solid tumors poses significant challenges, including tumor infiltration and trafficking difficulties, cytokine release syndrome, on-target offtumor toxicity, and T-cell exhaustion within the complex tumor microenvironment (38, [169][170][171][172].Till date, various types of combination immunotherapies have been studied, such as CAR-T cell with anti PD-L1 (173), double immune checkpoint inhibitor therapy such as anti PD-1/PD-L1 plus anti-CTLA-4 (174), and CAR-T cells with anti PD-1 (175). In a study by Cheng et al. (2023) combination of 4-1BB CAR-T and autocrine anti PD-L1 scFv improved the anti-tumor response of CAR-T cells along with improved persistence. ...
Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.
... The next important group of endothelial activation biomarkers are endothelial adhesion molecules, which are expressed on the surface of endothelial and other cells and play a crucial role in the interaction and adhesion of leukocytes, other cells, and the ECM to the endothelium (94,95). Endothelial adhesion molecules play dual roles in stabilizing and destabilizing the endothelium and also in controlling the contact between CAR T cells and their targets (96). Under normal physiological conditions, they contribute to the maintenance of vascular integrity and homeostasis by regulating leukocyte recruitment and transendothelial migration. ...
... Under normal physiological conditions, they contribute to the maintenance of vascular integrity and homeostasis by regulating leukocyte recruitment and transendothelial migration. However, in pathological conditions such as inflammation, infection, or cancer, excessive or prolonged expression of adhesion molecules can lead to endothelial destabilization, increased vascular permeability, and leukocyte infiltration (96,97). To highlight only a few of the important examples of adhesion molecules, Intercellular Adhesion Molecule-1 (ICAM-1), angiopoietin-2 (Ang-2), Vascular Cell Adhesion Molecule-1 (VCAM-1), and others contribute to endothelial permeabilization. ...
... Another significant component of biomarkers of the immune system pertains to the antitumor cytotoxic activity of the CAR T cells. The mechanisms entailing migration, tumor cell recognition, cytokine release, and target cell killing are highly complex and play key roles in successful antitumor efficacy of CAR T cells after administration of the cell product into the patient (10,96,122,123). The specific steps of the cytotoxic function are shown in Figure 3. Any malfunctions within these cytotoxic mechanisms can lead to unsuccessful therapy and severe inflammation. ...
Chimeric antigen receptor (CAR) T cell therapy holds enormous potential for the treatment of hematologic malignancies. Despite its benefits, it is still used as a second line of therapy, mainly because of its severe side effects and patient unresponsiveness. Numerous researchers worldwide have attempted to identify effective predictive biomarkers for early prediction of treatment outcomes and adverse effects in CAR T cell therapy, albeit so far only with limited success. This review provides a comprehensive overview of the current state of predictive biomarkers. Although existing predictive metrics correlate to some extent with treatment outcomes, they fail to encapsulate the complexity of the immune system dynamics. The aim of this review is to identify six major groups of predictive biomarkers and propose their use in developing improved and efficient prediction models. These groups include changes in mitochondrial dynamics, endothelial activation, central nervous system impairment, immune system markers, extracellular vesicles, and the inhibitory tumor microenvironment. A comprehensive understanding of the multiple factors that influence therapeutic efficacy has the potential to significantly improve the course of CAR T cell therapy and patient care, thereby making this advanced immunotherapy more appealing and the course of therapy more convenient and favorable for patients.
... their contact with tumor cells [8][9][10] . Interestingly, such a hostile TME can also prevent the infiltration of CD8 + CAR T cells 11,12 , thus limiting the effectiveness of immunotherapy approaches based on CAR T cell infusion for solid cancer patients. Beyond extracellular determinants, intracellular factors also play an important role in the ability of T cells to migrate and reach tumor cells. ...
The ability of CD8⁺ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8⁺ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8⁺ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8⁺ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8⁺ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
... We previously reported that several TME elements, such as pro-tumoral macrophages and extracellular matrix fibers, can sequester CD8 + T cells in stromal areas, thus preventing their contact with tumor cells [8][9][10] . Interestingly, such a hostile TME can also prevent the infiltration of CD8 + CAR T cells 11,12 , thus limiting the effectiveness of immunotherapy approaches based on CAR T cell infusion for solid cancer patients. Beyond extracellular determinants, intracellular factors also play an important role in the ability of T cells to migrate and reach tumor cells. ...
The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a much minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cells intra-tumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
... As a result, CD28, a co-stimulatory receptor on T cells, cannot bind these ligands and contribute to T cell activation. In addition, CAR-T cell exposure to chronic antigen stimulation leads to further upregulation of PD-1 and PD-L1 [82,83], resulting in hyporesponsive T cells and enhancement of immunosuppressive Treg function [1]. ...
... The T cell motility and effector functions are a highly energy-demanding process and, therefore, modulated by the availability of several nutrients, such as glucose, glutamine, tryptophane, and arginine [83]. The high metabolic activity of the tumor cells reduces glucose and oxygen availability and causes the accumulation of lactic acid and other toxic metabolites in the TME. ...
... Consequently, T cell metabolism is constrained and the cells are nutrient deprived. Additionally, T cells suffer from oxidative stress due to hypoxia [1,24,83]. ...
Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.
... CAR-T cell therapy, as 'the living drug,' is different from other immunotherapies because CAR-T cell therapy is more susceptible to the immunosuppressive TME that limits its efficacy. There is ample evidence that soluble factors, including IDO, IL-10, TGF-β [79], and immune checkpoints, such as PD-1 and CTLA-4 [80], cause T cell dysfunction. Furthermore, trafficking of CAR-T cells into the TME, aberrant tumor vasculature, and suppression of CAR-T cells due to immunosuppressive cells are some key challenges that the TME poses to CAR-T cells. ...
Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CART cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CART cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CART cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CART cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CART cell therapy to overcome immunosuppressive TME and improve the efficacy of CART cell therapy in the treatment of MM.
... While these humoral and cellular immunotherapy options are highly efficient in B-cell leukemias, their application is limited for the treatment of solid tumors which may be due to mechanical barriers, the lack of expression of suitable homing receptors and adhesion molecules which interferes with an efficient infiltration of immune cells into tumor tissues. Moreover, the immunosuppressive tumor microenvironment including the expression of check point inhibitors leads to a downregulation of infiltrated immune effector cells (e.g., [11][12][13]). ...
Radiation of tumor cells can lead to the selection and outgrowth of tumor escape variants. As radioresistant tumor cells are still sensitive to retargeting of T cells, it appears promising to combine radio- with immunotherapy keeping in mind that the radiation of tumors favors the local conditions for immunotherapy. However, radiation of solid tumors will not only hit the tumor cells but also the infiltrated immune cells. Therefore, we wanted to learn how radiation influences the functionality of T cells with respect to retargeting to tumor cells via a conventional bispecific T cell engager (BiTE) and our previously described modular BiTE format UNImAb. T cells were irradiated between 2 and 50 Gy. Low dose radiation of T cells up to about 20 Gy caused an increased release of the cytokines IL-2, TNF and interferon-γ and an improved capability to kill target cells. Although radiation with 50 Gy strongly reduced the function of the T cells, it did not completely abrogate the functionality of the T cells.
As the lowest organisms possessing T cells, fish are instrumental for understanding T cell evolution and immune defense in early vertebrates. This study established in Nile tilapia models suggests that T cells play a critical role in resisting Edwardsiella piscicida infection via cytotoxicity and are essential for IgM+ B cell response. CD3 and CD28 monoclonal antibody crosslinking reveals that full activation of tilapia T cells requires the first and secondary signals, while Ca2+–NFAT, MAPK/ERK, NF‐κB, and mTORC1 pathways and IgM+ B cells collectively regulate T cell activation. Thus, despite the large evolutionary distance, tilapia and mammals such as mice and humans exhibit similar T cell functions. Furthermore, it is speculated that transcriptional networks and metabolic reprogramming, especially c‐Myc‐mediated glutamine metabolism triggered by mTORC1 and MAPK/ERK pathways, underlie the functional similarity of T cells between tilapia and mammals. Notably, tilapia, frogs, chickens, and mice utilize the same mechanisms to facilitate glutaminolysis‐regulated T cell responses, and restoration of the glutaminolysis pathway using tilapia components rescues the immunodeficiency of human Jurkat T cells. Thus, this study provides a comprehensive picture of T cell immunity in tilapia, sheds novel perspectives for understanding T cell evolution, and offers potential avenues for intervening in human immunodeficiency. Fish represent the lowest extant animals to possess T cells. Despite large evolutionary distance, tilapia share similar T cell function with mammals. Metabolic reprogramming, especially c‐Myc‐mediated glutamine metabolism, which is conserved across tilapia, frogs, chickens, and mice, underlies functional similarity of T cells between tilapia and tetrapods. Rebuilding glutaminolysis pathways using tilapia components rescues the immunodeficiency of human T cells.
