Search Results (228)

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

Stage IV colorectal cancer has a poor prognosis, and liver metastases are prone to recurrence, even after resection. This study aimed to identify common cancer antigens, using immunohistochemical staining, as promising targets for antigen-specific immunotherapies in colorectal cancer. We analyzed expression levels and intracellular localization of seven common cancer antigens, CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC, and human leukocyte antigen (HLA) class I via immunohistochemical staining of 85 surgical specimens from primaries and liver metastases. Staining intensity and positive staining were scored to evaluate antigen expression. In 25 primaries, seven cancer antigens were expressed in 88–96% of cases, while HLA class I was expressed on the cell membrane in 80.0% of cases. In 60 liver metastases, FOXM1 and SPARC expression were approximately half that observed in the primaries. Other antigens and HLA class I were highly expressed in both. Most of the primaries and liver metastases may benefit from chimeric antigen receptor-T cell therapy targeting CLDN1, EphB4, and LAT1. Cases with high HLA class I expression may be suitable for vaccine-based and T cell receptor-T cell therapy targeting CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC for primaries and targeting antigens, excluding FOXM1 and SPARC, for liver metastases. Full article

It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T lymphocyte signaling functions induced by chronic hyperglycemia. In this study we have utilized the established UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model of human T2DM to investigate whether progressive hyperglycemia diminishes T cell receptor (TCR)-releasable endoplasmic reticulum (ER) Ca²⁺ stores, an essential early antigen-stimulated signal driving T cell activation. Furthermore, results from this study demonstrate that chronic hyperglycemia markedly alters the expression profile of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) Ca²⁺ ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca²⁺ pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca²⁺ store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca²⁺ signal dysregulation. In summary, these experiments suggest that hyperglycemia in T2DM drives an ER stress state manifesting in reduced expression of the SERCA pumps, erosion of ER Ca²⁺ stores and culminating in T cell and immune dysfunction. Full article

Background/Objectives: The physiological activation of cytotoxic CD8^pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARG^TPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARG^TPR makes them recognizable for pre-existing anti-CMV_pp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARG^TPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARG^TPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARG^TPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways. Full article

T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide–MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = −0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capacity, characterized by broadened epitope recognition and more effective suppression of HTLV-1 infection. To our knowledge, this is the first study to systematically quantify TCR degeneracy in HTLV-1-specific CTLs and evaluate its contribution to viral control in HAM patients. These findings establish TCR degeneracy as a critical determinant of antiviral efficacy and provide a novel immunological insight into the mechanisms of viral suppression in chronic HTLV-1 infection. Full article

Chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-engineered T-cell (TCR-T) therapies have revolutionized the treatment of hematological malignancies; however, their application to solid tumors remains a formidable challenge. The immunosuppressive tumor microenvironment, antigen heterogeneity, and manufacturing complexity limit the clinical efficacy and scalability of these treatment modalities. This review provides a comprehensive analysis of the current clinical development strategies for CAR-T and TCR-T cell therapies for solid tumors. Herein, we discuss recent breakthroughs and highlight the potential of TCR-T cell therapy. Furthermore, innovative approaches for enhancing CAR-T cell function in solid tumors (e.g., in vivo engineering; induced pluripotent stem cell-derived allogeneic CAR-T cells; armored CAR constructs; dual-antigen targeting; and combination regimens with checkpoint inhibitors, chemotherapy, radiotherapy, and oncolytic viruses) are explored. We also present trends in global patent activity, revealing a marked acceleration in CAR-T- and TCR-T-related innovations, with the United States and China leading with respect to application volumes. This field is increasingly characterized by multidisciplinary collaborations between academia and industry, driving the development of next-generation platforms, including messenger RNA-based and off-the-shelf cell therapies. Although no CAR-T product has been approved for solid tumors, these findings underscore the accelerating momentum and translational promise of adoptive cell therapies. Addressing the unique biological and logistical challenges of solid tumors is essential for realizing the full potential of these transformative immunotherapies. Full article

Hypersensitivity reactions are dysregulated and potentially devastating immune responses, characterized by a tendency to become chronic. They target either self-proteins or harmless foreign proteins and are driven by both T and B cells. Although numerous symptomatic treatment options for hypersensitivity reactions have been established over recent decades, only a few antigen-specific, causal approaches capable of specifically targeting the pathogenic autoreactive T and/or B cells have been developed. Among these are cell-based treatment modalities involving chimeric antigen receptor (CAR)- or chimeric autoantibody-receptor (CAAR)-expressing cells. These therapies utilize B- or T-cell antigens, presented as B-cell epitopes or peptide-major histocompatibility complexes (pMHCs) to serve as bait. The latter are coupled to potent activation domains derived from the TCR/CD3 complex itself, such as the zeta or CD3 chains, as well as domains from bona fide co-stimulatory molecules (e.g., CD28, 4-1BB). Recent in vitro and in vivo studies have demonstrated the therapeutic potential of these ATMP-based strategies in eliminating autoreactive lymphocytes and alleviating hypersensitivity reactions. This systematic review provides a comprehensive overview of the current status of antigen-specific CAR and CAAR T-cell therapies, highlighting novel directions as well as the ongoing challenges within this promising research field. Full article

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied—among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide–HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis. Full article

The systemic treatment of breast cancer has evolved remarkably over the past decades. With the introduction of immune checkpoint inhibitors (ICIs), clinical outcomes for solid tumor malignancies have significantly improved. However, in breast cancer, the indication for ICIs is currently limited to triple-negative breast cancer (TNBC) only. In high-risk luminal B hormone receptor-positive (HR+) breast cancer (BC) and HER2-positive (HER2+) BC, modest efficacy of ICI and chemotherapy combinations were identified in the neoadjuvant setting. To address the unmet need, several novel immunotherapy strategies are being tested in ongoing clinical trials as summarized in the current review: bispecific antibodies, chimeric antigen receptor T-cell therapy (CAR-T), T-cell receptors (TCRs), tumor-infiltrating lymphocytes (TILs), tumor vaccines, and oncolytic virus therapy. Full article

Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease. Full article

UVB phototherapy effectively treats psoriasis. Although it suppresses both innate and adaptive immunity, it remains unclear why UVB irradiation is primarily effective for T-cell-mediated but not inflammatory skin diseases of other etiologies. Using a Vα3S1/Vβ13S1 T-cell receptor (TCR) from a lesional psoriatic CD8⁺ T-cell clone, we recently demonstrated that in psoriasis, the major psoriasis risk allele HLA-C*06:02 mediates an autoimmune response of CD8⁺ T-cells against melanocytes by presenting a melanocyte autoantigen. We now investigate the effect of UVB irradiation on melanocyte immunogenicity using the psoriatic Vα3S1/Vβ13S1 TCR in a reporter assay. The immunogenicity of melanocytes for the Vα3S1/Vβ13S1 TCR depended on the up-regulation of HLA-C expression by IFN-γ. UVB irradiation reduced the stimulatory capacity of IFN-γ-conditioned melanocytes for the Vα3S1/Vβ13S1 TCR by suppressing key IFN-γ-induced MHC-class I transcriptional regulators (STAT1, IRF1, NLRC5), the HLA-C-specific transcription factor Oct1, and by inducing miR-148a, which specifically inhibits HLA-C expression. This resulted in the suppression of the IFN-γ-induced expression of HLA-class I molecules and, in particular, an almost complete loss of HLA-C expression. We conclude that suppression of the inflammatory increase in HLA-class I expression and antigen-presentation may contribute to the efficacy of UVB phototherapy in T-cell-mediated skin diseases. The pronounced downregulation of HLA-C on melanocytes could render psoriasis, as HLA-C-associated disease, particularly susceptible to this effect. Full article

The rapid increase in colorectal cancer (CRC) cases recently has highlighted the need to use predictive biomarkers to guide therapeutic approaches. Current studies have focused on the tumor-infiltrating lymphocytes present in the tumor microenvironment (TME), in which cytotoxic T cell activation and the amount are associated with CRC patient prognosis. The T cell receptor (TCR) is essential for antigen recognition and T cell identification, playing a central role in cancer immunotherapy. The T cell status reflects TCR diversity or clonality, known as the TCR repertoire. Accordingly, analyzing the TCR repertoire dynamics may help predict the immunological circumstances of the TME in a timely way. In this review, we summarize the TCR repertoire-related knowledge, including its potential use as predictive biomarkers in CRC. The intratumoral TCR repertoire is restricted in CRC patients compared with healthy individuals, as well as in peripheral blood. Patients with deficient mismatch repair display more restriction than those with proficient mismatch repair. Importantly, a higher TCR diversity before treatment and a decrease following treatment may indicate a good response and a better clinical outcome in CRC patients. The future use of TCR repertoire sequencing technology combined with artificial intelligence-based analysis is a potential strategy for CRC therapeutic decision making. Full article

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL), a hematological malignancy, and HTLV-1-associated myelopathy (HAM), a progressive neurological disorder. HTLV-1 predominantly infects CD4+ T cells in vivo. The T-cell receptor (TCR)/CD3 complex on CD4+ helper T cells plays a pivotal role in immune responses by recognizing antigens and facilitating coordination with other immune cells. Dysfunction of the TCR/CD3 complex may impair immune function. Although CD3 downregulation has been identified as a characteristic of ATL cells, it remains uncertain whether a similar downregulation occurs in HTLV-1-infected cells from HAM patients. We hypothesized that HTLV-1 infection leads to TCR and CD3 downregulation, contributing to immune dysfunction in HAM patients. To test this hypothesis, we analyzed TCR/CD3 expression, TCR signaling, and immune responses in HTLV-1-infected cells from HAM patients. Intracellular HTLV-1 Tax detection revealed that HTLV-1 preferentially targets CD4+ over CD8+ T cells. CD3 and TCR expression levels were significantly lower in CD4+ T cells from HAM patients compared to healthy controls. Furthermore, HTLV-1-infected cells exhibited markedly reduced CD3 and TCR expression compared to uninfected cells. Impairments in TCR signaling, assessed through Lck and ZAP70 phosphorylation upon CD3 stimulation, were observed in CD4+ T cells from HAM patients compared to those from healthy controls. Notably, this reduction in TCR signaling was more pronounced in HTLV-1-infected CD4+ T cells than in uninfected CD4+ T cells in HAM patients. Additionally, cytomegalovirus (CMV)-specific CD4+ T cells detected by an addition of CMV antigens demonstrated reduced interferon-γ production in HTLV-1-infected cells compared to their uninfected counterparts. These findings suggest that TCR/CD3 downregulation and impaired TCR signaling contribute to immune dysfunction in HTLV-1-infected CD4+ T cells. As CD4+ T cells play a central role in immune responses, this mechanism may partially explain the cellular immune dysfunction to other pathogens observed in HAM patients. Full article

With the success of chimeric antigen receptor (CAR) T-cell therapy in B-cell malignancies, efforts are being made to extend this therapy to other malignancies and broader patient populations. However, limitations associated with the time-consuming and highly personalized manufacturing of autologous CAR T-cells remain. Allogeneic CAR T-cell approaches may overcome these challenges but require further engineering to reduce their alloreactivity. As a means to prevent graft-versus-host disease (GvHD) of allogeneic CAR T-cells, we have selected a micro RNA (miRNA)-based short hairpin RNA (shRNA) targeting CD3ζ which efficiently downregulates the expression of the T-cell receptor (TCR) below detection level. We generated allogeneic anti-B-cell maturation antigen CAR T-cells (CYAD-211) that co-express an anti-CD3ζ miRNA-based shRNA within the CAR construct which efficiently inhibited TCR-mediated signaling in vitro and GvHD in vivo. CYAD-211 was subsequently evaluated in a Phase-I clinical trial (NCT04613557), in patients with relapsed or refractory multiple myeloma. No signs of GvHD were observed despite evidence of engraftment, demonstrating efficient downregulation of the TCR. Our data provide proof of concept that a non-gene-edited technology can generate fully functional allogeneic CAR T-cells, without any signs of GvHD. However, further engineering of the CAR T-cells is needed to improve their persistence and long-term activity. Full article

Pancreatic cancer has the lowest 5-year survival rate (13%) among major cancers and is the third leading cause of cancer-related deaths in the United States. The high lethality of this cancer is attributed to its insidious onset, late-stage diagnosis, rapid progression, and limited treatment options. Addressing these challenges requires a deeper understanding of the complex tumor microenvironment to identify novel therapeutic targets. Newer approaches like adoptive cell therapy have shown remarkable success in treating hematological malignancies, but their application in solid tumors, particularly pancreatic cancer, is still in the early stages of development. ACT broadly involves isolating immune cells (T lymphocytes, Natural Killer cells, and macrophages) from the patient, followed by genetic engineering to enhance and mount a specific anti-tumor response. Various ACT modalities are under investigation for pancreatic cancer, including chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor NK cells (CAR-NK), tumor-infiltrating lymphocytes (TIL), T-cell receptor (TCR)-engineered T cells, and cytokine-induced killer cells (CIK). Major hurdles have been identifying actionable tumor antigens and delivering focused cellular therapies to overcome the immunosuppressive and dense fibrotic stroma surrounding the pancreatic cancer. Further studies are needed to explore the limitations faced by cellular therapy in pancreatic cancer and identify novel combination treatment approaches in order to improve clinical outcomes. Full article