Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers
and strategies to augment clinical response have largely focused on the T cell ...compartment. However, other immune subsets may also contribute to anti-tumour immunity
, although these have been less well-studied in ICB treatment
. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling
that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter
) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
A high tumour mutational burden (hypermutation) is observed in some gliomas
; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly ...understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune‐based therapies to succeed, T cell subsets with ...the correct tumor‐targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen‐specific T cell populations. While straightforward in principle, experience has shown that manipulation of the antigen presentation process can be incredibly complex, necessitating sophisticated strategies that are difficult to translate. Herein, the design of a biomimetic nanoparticle platform is reported that can be used to directly stimulate T cells without the need for professional antigen‐presenting cells. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells engineered to express a co‐stimulatory marker. Combined with the peptide epitopes naturally presented on the membrane surface, the final formulation contains the necessary signals to promote tumor antigen‐specific immune responses, priming T cells that can be used to control tumor growth. The reported approach represents an emerging strategy that can be used to develop multiantigenic, personalized cancer immunotherapies.
Cancer cells are genetically engineered to express a co‐stimulatory marker that enables them to directly present their own antigens under an immunostimulatory context. Cell‐membrane‐coated nanoparticles sourced from these modified cells elicit antitumor immunity in vivo while bypassing the need for traditional cell‐mediated antigen presentation. This approach may ultimately enable the facile design of personalized artificial antigen presentation platforms.
Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)‐camouflaged hollow MnO2 (HMnO2) catalytic nanosystem ...embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long‐circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O2, which can be produced during the decomposition of endogenous H2O2 catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti‐PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.
A strategy based on intra/extracellular lactic acid exhaustion is reported to achieve synergistic metabolic therapy and immunotherapy of tumors. This strategy is performed by a cascade catalytic nanosystem (PMLR) that integrates a hollow MnO2 nanocarrier with lactate oxidase and a glycolysis inhibitor.
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Combination therapy, integrating multiple merits of monotherapy into one platform for enhanced antitumor efficacy while eliminating the likelihoods of tumor recurrence and metastasis, ...is of particular interest in clinical application. Hydrogels self-assembled by biologically-based building blocks can be used as promising platforms for incorporation of one or more therapeutic drugs to gain additive or synergistic therapeutic functions. Herein, antitumor combination therapy based on injectable collagen/alginate hydrogels is achieved by simultaneous encapsulation of the photothermal drug methylene blue (MB) and immunological agent imiquimod (R837). The resulting hybrid hydrogel (Gel-MB-R837) with shear-thinning and self-healing properties is applicable for localized delivery and prolonged release of therapeutic drugs. The antitumor efficacy can be significantly enhanced by combinatorial photothermal therapy (PTT) and immunotherapy treatments through the synergy of MB and R837. Moreover, the initial PTT not only eradicates primary tumors, but also generates tumor-associated antigens (TAA), which combines with R837 to trigger immune response for further inhibiting tumor recurrence and metastasis. Therefore, the biocompatible hybrid hydrogels starting from naturally-occurring biomacromolecules offer promising prospects for combinatorial photothermal and immuno tumor therapy.
Blockade of the protein–protein interaction between the transmembrane protein programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 has emerged as a promising immunotherapy for treating ...cancers. Using the technology of mirror‐image phage display, we developed the first hydrolysis‐resistant D‐peptide antagonists to target the PD‐1/PD‐L1 pathway. The optimized compound DPPA‐1 could bind PD‐L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor‐bearing mice experiments indicated that DPPA‐1 could also effectively disrupt the PD‐1/PD‐L1 interaction in vivo. Thus D‐peptide antagonists may provide novel low‐molecular‐weight drug candidates for cancer immunotherapy.
Protein chemical synthesis and mirror‐image phage display were combined to develop a proteolysis‐resistant D‐peptide antagonist (DPPA‐1) which targets the immune checkpoint protein PD‐L1 (the ligand for PD‐1, the programmed cell death protein 1). DPPA‐1 was found to inhibit the PD‐1/PD‐L1 protein–protein interaction at the cellular level. IgV=immunoglobulin‐like variable.
Tumor fibrotic stroma forms complex barriers for therapeutic nanomedicine. Although nanoparticle vehicles are promising in overcoming biological barriers for drug delivery, fibrosis causes hypoxia, ...immunosuppression and limited immunocytes infiltration, and thus reduces antitumor efficacy of nanosystems. Herein, we report the development of cancer‐associated fibroblasts (CAFs) responsive honeycomb‐like nanoassemblies of carbon dots (CDs) to spatially program the delivery of multiple therapeutics for enhanced antitumor chemoimmunotherapy. Doxorubicin (DOX) and immunotherapeutic enhancer (Fe ions) are immobilized on the surface of CDs, whereas tumor microenvironment modifier (losartan, LOS) is encapsulated within the mesopores. The drugs‐loaded nanoassemblies disassociate into individual CDs to release LOS to mitigate stroma and hypoxia in response to CAFs. The individual CDs carrying DOX and Fe ion efficiently penetrate deep into tumor to trigger intensified immune responses. Our in vitro and in vivo studies show that the nanoassemblies exhibit effective T cells infiltration, tumor growth inhibition and lung metastasis prevention, thereby providing a therapeutic platform for desmoplasia solid tumor.
Cancer‐associated fibroblasts‐responsive honeycomb‐like nanoassemblies of carbon dots are fabricated to program the sequential and spatiotemporal release of multiple therapeutic agents for synergetic chemoimmunotherapy of cancer.
Immune checkpoint PD-1/PD-L1 blockade has emerged as a successful immunotherapy strategy for treating several types of malignant tumors. A constant and proper drug concentration during the treatment ...is important because the long-term activation of the immune system is urgently needed to perdurably recognize and attack cancer cells for a better therapeutic effect with minimum side effects. However, practically few related studies have been reported to date. In this study, we constructed a therapeutic strategy combining PD-1 blocking with photothermal ablation for malignant tumors by co-encapsulating anti-PD-1 peptide (APP) and hollow gold nanoshell (HAuNS) into biodegradable Poly (d, l-lactic-co-glycolide) nanoparticles (APP- and HAuNS-loaded PLGA nanoparticles, AA@PN). Slow and continuous release of APP from AA@PN could be obtained from 0 to 40 days, and this release was easily accelerated by illumination with a near-infrared (NIR) laser. A clear killing effect on distant tumor cells was observed after treatment of the co-culture system of PMBCs and tumor cells with AA@PN plus an NIR laser, reflecting the activated immune response. AA@PN followed by multiple irradiations with an NIR laser showed the strongest antitumor effect, with the elimination of most primary tumors compared with other treatments, and significantly inhibited the growth of the distant uninjected primary tumors, similarly to free APP with frequent injections, which induced the longest survival time for the mice in this group.
Preparation and structure of AA@PN as well as its combined therapeutic modalities. Display omitted
Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence
. Patient-derived CAR T cells have demonstrated remarkable efficacy ...against a range of B-cell malignancies
, and the results of early clinical trials suggest activity in multiple myeloma
. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low
. Unlike the mechanisms that result in complete and permanent antigen loss
, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.
Modulating the hostile tumor microenvironment (TME) rather than directly killing cancer cells may be an effective strategy to improve the therapeutic benefits in cancer treatment. Herein, FeWOX ...nanosheets are constructed as cascade bioreactors to modulate the TME and enhance radiotherapy and immunotherapy of tumors. Synthesized by the thermal‐decomposition method and modified by poly(ethylene glycol) (PEG), the obtained FeWOX‐PEG with multivalent metal elements (Fe2+/3+, W5+/6+) exhibit efficient catalytic decomposition of hydrogen peroxide (H2O2) to generate hydroxyl radicals (•OH) for chemo‐dynamic therapy (CDT). The generated high valence of metal ions (Fe3+/W6+) in FeWOX‐PEG are reduced by endogenous glutathione (GSH), both leading to depletion of GSH and further amplified oxidative stress, and resulting in the reduced metal valence statuses (Fe2+/W5+) enabling cascade bioreactions. Such FeWOX‐PEG bioreactors enhance the oxidative stress in the tumor and interact with X‐rays, significantly improving cancer radiotherapy (RT). Furthermore, the reactive oxygen species (ROS)‐induced inflammation caused by FeWOX‐PEG in TME activates the immune system and promotes the tumor‐infiltration of various types of immune cells, which working together with cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) checkpoint blockade could elicits a robust immune response to defeat tumors.
This work presents an intelligent cascade bioreactor based on multivalent bimetallic oxide FeWOX nanosheets, which exhibit efficient catalytic decomposition of hydrogen peroxide (H2O2) to generate hydroxyl radicals (•OH), as well as glutathione depletion capability to further amplify oxidative stress. This good tumor microenvironment‐modulation performance can further enhance both radiotherapy and immunotherapy of tumors.
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