Oncoimmunology最新文献

Antibody-epitope conjugates (AECs) proved to be a promising new therapeutic strategy to redirect virus-specific CD8⁺ T cells toward cancer cells by delivering T-cell epitopes. To be able to redirect a larger fraction of the virus-specific T-cell population, it is beneficial to deliver a broader selection of T-cell epitopes. We investigated two different methods to generate AECs with two distinct virus-specific T-cell epitopes fused to one antibody. Epitopes were either placed in a tandem-like fashion at the C-terminus of the AEC (t-AEC) or bispecific-AECs (bs-AECs) were generated via controlled Fab-arm exchange to generate bs-AECs with two identical antigen binding domains, but two distinct epitopes on each Fab-arm. Our study revealed that maintaining a free epitope terminus was required for efficient delivery of the virus-specific T-cell epitopes. Consequently, viral-epitope delivery using t-AECs was suboptimal as the concatenated epitopes were less effectively delivered to the target cells. However, well-defined bs-AECs containing both CMV and EBV epitopes were successfully generated and both in vitro and in vivo efficacy was evaluated. Our results demonstrate that bispecific-AECs can efficiently deliver EBV and CMV epitopes simultaneously to multiple cancer cell lines from different origins, thereby redirecting and activating two distinct populations of virus-specific T cells. Furthermore, our in vivo findings indicate that when both virus-specific T-cell populations are present and tumor cells express the proteases required for efficient epitope delivery, bs-AECs exhibit similar efficacy in reducing tumor burden compared to AECs. To conclude, our study demonstrates the feasibility of redirecting two groups of virus-specific T cells using a single antibody and highlights the potential of bs-AECs both in vitro and in vivo.

In multiple myeloma (MM), the anti-CD38 monoclonal antibody Daratumumab has become essential in the therapeutic arsenal, although very few predictive factors of response to Daratumumab have been identified in clinical studies. We have prospectively collected biological data from 97 patients treated with Daratumumab in first line or at relapse in our center between 2016 and 2020. These data included multiparameter flow cytometry phenotype (CD200, CD117, CD56, CD38, CD45, and CD27), cytogenetic, and transcriptomic gene expression profiling (GEP) of tumor plasma cells before treatment with Daratumumab. We first looked for predictive factors of response to Daratumumab. We found that high CD56 expression and CD45 expression were significantly associated with better progression free survival (PFS) whereas high CD200 expression was significantly associated with poorer PFS. Then, we showed that the CD200-CD200R immune synapse is responsible for a decrease in Daratumumab response through the alteration of NK cells' activity. Finally, we demonstrated that inhibition of CD200 increase response to Daratumumab in MM patient samples, highlighting its potential as a predictive biomarker for Daratumumab response and as a possible therapeutic target in combination with Daratumumab. This study is the first to identify phenotypic and molecular factors' predictor of response to Daratumumab.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy by enhancing anti-tumor immune responses, yet their use can lead to immune-related adverse events (irAE), including neurological complications. Despite their clinical relevance, predictive biomarkers for irAE remain scarce, and early identification of at-risk patients is a major unmet need. In this prospective study, 200 patients undergoing ICI therapy were enrolled, of whom 59 underwent longitudinal metabolomic profiling at baseline, three months, and six months. Thirty-two patients who developed irAE were compared to 27 age- and sex-matched individuals without irAE. Multivariate analyses, including Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA), revealed distinct metabolomic signatures differentiating the two groups. Notably, baseline levels of triglyceride 20:0_34:1 were significantly lower in irAE(+) patients. In female patients, additional triglyceride species-20:1_34:2, 20:2_34:2, and 20:2_34:3-were also reduced prior to therapy and showed increases within three months of ICI initiation. These findings suggest that specific triglyceride species may serve as early biomarkers for irAE risk, particularly in female patients. The observed dynamic changes point to a potential link between lipid metabolism and immune-related toxicity, supporting the integration of metabolomic profiling into future strategies for risk stratification and personalized monitoring in cancer immunotherapy.

Among adoptive cell-based immunotherapies, chimeric antigen receptor (CAR) therapy has shown promising results in cancer treatment. Treatment with CAR-T cells has produced remarkable clinical responses, especially in cases of relapsed and refractory leukemia and lymphoma. However, CAR-T cell therapy still presents several limitations, including some safety concerns related to neurotoxicity and aggressive inflammatory responses. As an alternative to T-cells, natural killer (NK) cells have been developed as an attractive option for efficient cancer immunotherapy. As they do not express T cell receptor (TCR), NK cell-based therapies are not associated with cytokine release syndrome (CRS) or graft versus host disease (GvHD), which enables a safer therapy and the ability to generate an allogeneic "off-the-shelf" product. Despite the innate cytotoxic activity of NK cells against malignant cells, the therapeutic application of unmodified NK cells has been compromised by the inhibitory tumor microenvironment (TME), which is responsible for poor cell expansion, inactivation, insufficient tumor infiltration, and limited in vivo persistence, leading to the dysfunction of NK cells after infusion. Advances in the genetic modification of NK cells can address some of these limitations and improve their therapeutic efficacy. In this review, we describe the advances in the development of engineered NK cells for cancer immunotherapy. As such, we provide an overview of recent viral and non-viral approaches for the genetic modification of NK cells. We also discuss their current clinical status in the field of immunotherapy, and their use in other clinical applications.

CAR-T cell therapy demonstrates significant efficacy in hematologic malignancies, with target selection critically determining therapeutic outcomes. However, the available tumor surface antigens are limited, especially in the treatment of solid tumors. A potential solution to overcome this limitation entails employing antibodies recognizing peptide-major histocompatibility complex (pMHC) structures, enabling CAR-T cell to detect intracellular tumor antigens through a T cell receptor (TCR)-like recognition mechanism. This study focuses on HBV-associated hepatocellular carcinoma (HBV-HCC), where HBV DNA integration into the host genome generates specific viral antigen epitopes presented by MHC class I molecules, representing attractive targets for CAR-T cell therapy. We engineered CAR-T cells with a TCR-like antibody (HBs183 CAR-T) specific for the immunodominant HBV envelope epitope Env183-191 presented by HLA-A *0201, and evaluated the antigen-specific cytotoxicity and safety profile of the CAR-T cells through in vitro functional assays and in vivo evaluation in heterogenous tumor models (subcutaneous and intraperitoneal xenografts). Our research provides a reference for CAR-T cell therapy targeting intracellular antigens, particularly specific antigens derived from viral infections, as targets for CAR-T treatment, and offers a preliminary concept validation for the CAR-T treatment of HBV-HCC tumors.

Immunotherapy has demonstrated potential in treating various malignant tumors, but its efficacy in pancreatic cancer (PC) remains limited, possibly due to the dense stromal components and immunosuppressive microenvironment of PC. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a crucial role in the tumor microenvironment and intracellular signaling pathways. However, the specific role of FAK in the development and progression of PC, as well as its regulatory mechanisms on the tumor immune microenvironment (TIM), are still not fully understood. In this study, we analyzed single-cell sequencing datasets and clinical specimens to evaluate the role of FAK in the immune response of PC. We verified the impact of FAK alterations on CD8⁺ T cell infiltration using a co-culture system of patient-derived organoids (PDO) and immune cells. Additionally, mouse PC models and dual humanized models are established to investigate the in vivo function of FAK and the potential of its inhibitors for immunotherapy. Our results demonstrate that FAK is associated with the immunosuppressive microenvironment in PC. Inhibiting FAK enhances CD8⁺ T cell infiltration by promoting CXCL10 secretion in PC. Moreover, FAK inhibitors exhibit a synergistic anti-tumor effect when combined with immune checkpoint inhibitors. This study explores the potential of FAK as a therapeutic target, particularly its role in modulating TIM, thereby providing new research directions for the treatment of PC.

HER3-DXd and T-DXd are antibody-drug conjugates (ADCs) that induce immunogenic cell death and bystander killing, enhancing antitumor immunity beyond target-specific cytotoxicity. These findings highlight novel mechanisms that can overcome antigen heterogeneity and suggest opportunities for improving ADC design and therapeutic synergy through informed combination with immunotherapies.

Cancer cell therapies have primarily focused on engineering autologous αβ T cells with chimeric antigen receptors (CARs), achieving clinical success against hematologic malignancies. However, their effectiveness against solid tumors is limited by challenges such as antigen escape, suppression by the metabolically hostile tumor microenvironment (TME), and manufacturing difficulties. γδ T cells are unconventional T cells with innate tumor-targeting capabilities independent of MHC class I, making them an emerging candidate for allogeneic cell therapy. While the Vδ1 T cell subset has shown promising anti-tumor killing their clinical application has been hindered by difficulties in achieving robust expansion for therapeutic use. Here, we evaluated the potential of K562 feeder cells expressing membrane-bound IL-21 (K562-mb-IL-21) to expand and activate γδ T cells from peripheral blood. Our findings show that this method preferentially expands Vδ1 T cells, resulting in an activated phenotype characterized by enhanced expression of NK cell activation receptors, innate cytotoxicity against breast and ovarian cancer cells, and sustained metabolic function in patient-derived ascites TME. When engineered with a CAR, Vδ1 T cells exhibited further enhanced anti-tumor efficacy in an immunodeficient NRG xenograft model of human ovarian cancer. These findings highlight K562-mb-IL-21 expanded peripheral blood Vδ1 T cells as a promising 'off-the-shelf' allogeneic therapy for solid tumors.

Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion - features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.

Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.