logo logo
T-Cell-Derived Nanovesicles for Cancer Immunotherapy. Hong Jihye,Kang Mikyung,Jung Mungyo,Lee Yun Young,Cho Yongbum,Kim Cheesue,Song Seuk Young,Park Chun Gwon,Doh Junsang,Kim Byung-Soo Advanced materials (Deerfield Beach, Fla.) Although T-cell therapy is a remarkable breakthrough in cancer immunotherapy, the therapeutic efficacy is limited for solid tumors. A major cause of the low efficacy is T-cell exhaustion by immunosuppressive mechanisms of solid tumors, which are mainly mediated by programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β). Herein, T-cell-derived nanovesicles (TCNVs) produced by the serial extrusion of cytotoxic T cells through membranes with micro-/nanosized pores that inhibit T-cell exhaustion and exhibit antitumoral activity maintained in the immunosuppressive tumor microenvironment (TME) are presented. TCNVs, which have programmed cell death protein 1 and TGF-β receptor on their surface, block PD-L1 on cancer cells and scavenge TGF-β in the immunosuppressive TME, thereby preventing cytotoxic-T-cell exhaustion. In addition, TCNVs directly kill cancer cells via granzyme B delivery. TCNVs successfully suppress tumor growth in syngeneic-solid-tumor-bearing mice. Taken together, TCNV offers an effective cancer immunotherapy strategy to overcome the tumor's immunosuppressive mechanisms. 10.1002/adma.202101110
Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1-mediated tumor eradication. The Journal of clinical investigation Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy. 10.1172/JCI155148
Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Martinez-Usatorre Amaia,Kadioglu Ece,Boivin Gael,Cianciaruso Chiara,Guichard Alan,Torchia Bruno,Zangger Nadine,Nassiri Sina,Keklikoglou Ioanna,Schmittnaegel Martina,Ries Carola H,Meylan Etienne,De Palma Michele Science translational medicine Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of ; NSCLC, including a mismatch repair-deficient variant ( ; ; ) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1 regulatory T cells (T), which were more efficiently targeted by the PD-1 antibody than CD8 T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-β-rich tumor microenvironment that supported PD-1 T Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated T, redirected the PD-1 antibody to CD8 T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors. 10.1126/scitranslmed.abd1616
LRRC15 myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15). However, the molecular signals that underlie the development of LRRC15 cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin universal fibroblasts is essential for the development of cancer-associated LRRC15 myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15 CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8 T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15 CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8 T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15 myofibroblasts may improve patient survival and response to immunotherapy. 10.1038/s41586-022-05272-1
Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Lan Yan,Moustafa Mahmoud,Knoll Maximilian,Xu Chunxiao,Furkel Jennifer,Lazorchak Adam,Yeung Tsz-Lun,Hasheminasab Sayed-Mohammad,Jenkins Molly H,Meister Sarah,Yu Huakui,Schlegel Julian,Marelli Bo,Tang Zili,Qin Guozhong,Klein Carmen,Qi Jin,Zhou Cheng,Locke George,Krunic Damir,Derner Melissa G,Schwager Christian,Fontana Rachel E,Kriegsmann Katharina,Jiang Feng,Rein Katrin,Kriegsmann Mark,Debus Juergen,Lo Kin-Ming,Abdollahi Amir Cancer cell Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8 T cells. Intriguingly, targeting of the TGF-β trap to PD-L1 endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation. 10.1016/j.ccell.2021.08.008
Tumour-intrinsic resistance to immune checkpoint blockade. Kalbasi Anusha,Ribas Antoni Nature reviews. Immunology 'Immune checkpoint blockade' for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT-β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade. 10.1038/s41577-019-0218-4
Regulation and Function of the PD-L1 Checkpoint. Sun Chong,Mezzadra Riccardo,Schumacher Ton N Immunity Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies. 10.1016/j.immuni.2018.03.014