Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation.

As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies.

OBJECTIVE: The human cluster of differentiation (CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer (NK) cells targeting hematologic malignancies (HMs). METHODS: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine (PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients. RESULTS: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS-CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an "exhausted" phenotype of intratumoral NK cells in patients with HMs or solid tumors. CONCLUSIONS: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

Enhancing Tumor Immunotherapy by Multivalent Anti-PD-L1 Nanobody Assembled via Ferritin Nanocage.

Increasing immunotherapy response rate and durability can lead to significant improvements in cancer care. To address this challenge, a novel multivalent immune checkpoint therapeutic platform is constructed through site-specific ligation of anti-PD-L1 nanobody (Nb) on ferritin (Ftn) nanocage. Nb-Ftn blocks PD-1/PD-L1 interaction and downregulates PD-L1 levels via endocytosis-induced degradation. In addition, the cage structure of Ftn allows encapsulation of indocyanine green (ICG), an FDA-approved dye. Photothermal treatment with Nb-Ftn@ICG induces immunogenic death of tumor cells, which improves systemic immune response via maturation of dendritic cells and enhanced infiltration of T cells. Moreover, Nb-Ftn encapsulation significantly enhances cellular uptake, tumor accumulation and retention of ICG. In vivo assays showed that this nanoplatform ablates the primary tumor, suppresses abscopal tumors and inhibits tumor metastasis, leading to a prolonged survival rate. This work presents a novel strategy for improving cancer immunotherapy using multivalent nanobody-ferritin conjugates as immunological targeting and enhancing carriers.

Clinical immunotherapy in pancreatic cancer.

Pancreatic cancer remains a challenging disease with limited treatment options, resulting in high mortality rates. The predominant approach to managing pancreatic cancer patients continues to be systemic cytotoxic chemotherapy. Despite substantial advancements in immunotherapy strategies for various cancers, their clinical utility in pancreatic cancer has proven less effective and durable. Whether administered as monotherapy, employing immune checkpoint inhibitors, tumor vaccines, chimeric antigen receptors T cells, or in combination with conventional chemoradiotherapy, the clinical outcomes remain underwhelming. Extensive preclinical experiments and clinical trials in the realm of pancreatic cancer have provided valuable insights into the complexities of immunotherapy. Chief among the hurdles are the immunosuppressive tumor microenvironment, limited immunogenicity, and the inherent heterogeneity of pancreatic cancer. In this comprehensive review, we provide an overview and critical analysis of current clinical immunotherapy strategies for pancreatic cancer, emphasizing their endeavors to overcome immunotherapy resistance. Particular focus is placed on strategies aimed at reshaping the immunosuppressive microenvironment and enhancing T cell-mediated tumor cell killing. Ultimately, through deeper elucidation of the underlying pathogenic mechanisms of pancreatic cancer and the refinement of therapeutic approaches, we anticipate breakthroughs that will pave the way for more effective treatments in this challenging disease.

Tumor-infiltrating platelets promote the growth of lung adenocarcinoma.

PURPOSE: Platelets could promote tumor growth and metastasis. However, the role of platelets in different subtypes of non-small cell lung cancer (NSCLC) and platelet infiltration in local tumor tissue remain unclear. METHODS: Initially, platelet infiltration in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) was estimated by CD41 expression using immunohistochemistry. Subsequently, co-incubation of NSCLC cell lines and platelets was performed to compare the ability of binding platelets. Subcutaneous tumor models were established to assess the ability of platelets to promote tumor growth. Then, RNA-seq data of NSCLC was used to identify differentially expressed genes and enriched pathways. Lastly, a clinical cohort comprising of ADC and SCC patients as well as meta-analysis was analyzed to compare the difference of coagulation associated clinical parameters. RESULTS: We found high platelet infiltration in ADC, especially of advanced disease and metastases, whereas few platelets were observed in SCC. Moreover, ADC cell lines exhibited strong ability of binding platelets compared with SCC cell lines. Platelets could also promote the growth of ADC cell lines in vivo. Furthermore, coagulation cascades and fibrinogen were upregulated in ADC. And chemical inhibition of GPIIb/IIIa-fibrinogen axis reduced the binding of ADC cells and platelets. ADC patients were also in a hypercoagulable state characterized by higher d-dimer level and shorter clotting time. Finally, meta-analysis identified a higher risk of venous thromboembolism (VTE) in ADC patients and low molecular weight heparin (LMWH) treatment was effective at reducing this risk. CONCLUSIONS: This study identified the differences of platelet infiltration and coagulation between ADC and SCC patients, which may inform the development of anticoagulation therapies for NSCLC.

Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that show a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK-signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK-STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

Tumors evade immune cytotoxicity by altering the surface topology of NK cells.

The highly variable response rates to immunotherapies underscore our limited knowledge about how tumors can manipulate immune cells. Here the membrane topology of natural killer (NK) cells from patients with liver cancer showed that intratumoral NK cells have fewer membrane protrusions compared with liver NK cells outside tumors and with peripheral NK cells. Dysregulation of these protrusions prevented intratumoral NK cells from recognizing tumor cells, from forming lytic immunological synapses and from killing tumor cells. The membranes of intratumoral NK cells have altered sphingomyelin (SM) content and dysregulated serine metabolism in tumors contributed to the decrease in SM levels of intratumoral NK cells. Inhibition of SM biosynthesis in peripheral NK cells phenocopied the disrupted membrane topology and cytotoxicity of the intratumoral NK cells. Targeting sphingomyelinase confers powerful antitumor efficacy, both as a monotherapy and as a combination therapy with checkpoint blockade.

LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia.

BACKGROUND: Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. METHODS: First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. RESULTS: Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. CONCLUSIONS: Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth.

Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD+ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non-histone proteins and suppress HCC development. Using SILAC-based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators.

TIPE2 deletion improves the therapeutic potential of adoptively transferred NK cells.

BACKGROUND: To enhance the efficacy of adoptive NK cell therapy against solid tumors, NK cells must be modified to resist exhaustion in the tumor microenvironment (TME). However, the molecular checkpoint underlying NK cell exhaustion in the TME remains elusive. METHODS: We analyzed the correlation between TIPE2 expression and NK cell functional exhaustion in the TME both in humans and mice by single-cell transcriptomic analysis and by using gene reporter mice. We investigated the effects of TIPE2 deletion on adoptively transferred NK cell therapy against cancers by using NK cells from NK-specific Tipe2-deficient mice or peripheral blood-derived or induced pluripotent stem cell (iPSC)-derived human NK cells with TIPE2 deletion by CRISPR/Cas9. We also investigated the potential synergy of double deletion of TIPE2 and another checkpoint molecule, CISH. RESULTS: By single-cell transcriptomic analysis and by using gene reporter mice, we found that TIPE2 expression correlated with NK cell exhaustion in the TME both in humans and mice and that the TIPE2 high NK cell subset correlated with poorer survival of tumor patients. TIPE2 deletion promoted the antitumor activity of adoptively transferred mouse NK cells and adoptively transferred human NK cells, either derived from peripheral blood or differentiated from iPSCs. TIPE2 deletion rendered NK cells with elevated capacities for tumor infiltration and effector functions. TIPE2 deletion also synergized with CISH deletion to further improve antitumor activity in vivo. CONCLUSIONS: This study highlighted TIPE2 targeting as a promising approach for enhancing adoptive NK cell therapy against solid tumors.

Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8+ T Cells.

Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8+ T-cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T-bet/Eomes-IFN-γ axis in NK cells is essential for CD8+ T cell-dependent tumor control, whereas T-bet-dependent NK cell effector functions are required for an optimal response to anti-PD-L1 immunotherapy. Importantly, NK cell-expressed TIPE2 (tumor necrosis factor-alpha-induced protein-8 like-2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK-intrinsic antitumor activity but also indirectly improves the antitumor CD8+ T cell response by promoting T-bet/Eomes-dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell-based immunotherapy.

Cytomegalovirus-specific neutralizing antibodies effectively prevent uncontrolled infection after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains one of the most frequent and life-threatening infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Herein, we comprehensively compared the immune cells of patients with uncontrolled and controlled CMV infection post-allo-HSCT and found that B-cells were extraordinarily insufficient because of impaired B-cells reconstitution in the uncontrolled infection group. Furthermore, in the controlled infection group, reconstructed B-cells showed signatures of mature B-cells, high expression of CXCR4 and IFITM1, and enrichment of CMV-associated B-cell receptors, which were lacking in the uncontrolled infection group. Consistently, sera from the uncontrolled infection group failed to inhibit CMV infection via neutralizing virus in vitro because of its lower content of anti-CMV-specific immunoglobulin G (IgG) than the controlled infection group. Overall, these results highlighted the contribution of B cells and anti-CMV-specific neutralizing IgGs to the restraint of CMV infection post-allo-HSCT, suggesting their potential as a supplementary treatment to improve outcomes.

GARP-mediated active TGF-ß1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT.

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor ß1 (TGF-ß1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-ß1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-ß1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-ß1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-ß1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-ß1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

Human-Induced CD49a+ NK Cells Promote Fetal Growth.

CD49a+ natural killer (NK) cells play a critical role in promoting fetal development and maintaining immune tolerance at the maternal-fetal interface during the early stages of pregnancy. However, given their residency in human tissue, thorough studies and clinical applications are difficult to perform. It is still unclear as to how functional human CD49a+ NK cells can be induced to benefit pregnancy outcomes. In this study, we established three no-feeder cell induction systems to induce human CD49a+ NK cells from umbilical cord blood hematopoietic stem cells (HSCs), bone marrow HSCs, and peripheral blood NK cells in vitro. These induced NK cells (iNKs) from three cell induction systems display high levels of CD49a, CD9, CD39, CD151 expression, low levels of CD16 expression, and no obvious cytotoxic capability. They are phenotypically and functionally similar to decidual NK cells. Furthermore, these iNKs display a high expression of growth-promoting factors and proangiogenic factors and can promote fetal growth and improve uterine artery blood flow in a murine pregnancy model in vivo. This research demonstrates the ability of human-induced CD49a+ NK cells to promote fetal growth via three cell induction systems, which could eventually be used to treat patients experiencing adverse pregnancy outcomes.

Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond.

Histological imaging is essential for the biomedical research and clinical diagnosis of human cancer. Although optical microscopy provides a standard method, it is a persistent goal to develop new imaging methods for more precise histological examination. Here, we use nitrogen-vacancy centers in diamond as quantum sensors and demonstrate micrometer-resolution immunomagnetic microscopy (IMM) for human tumor tissues. We immunomagnetically labeled cancer biomarkers in tumor tissues with magnetic nanoparticles and imaged them in a 400-nm resolution diamond-based magnetic microscope. There is barely magnetic background in tissues, and the IMM can resist the impact of a light background. The distribution of biomarkers in the high-contrast magnetic images was reconstructed as that of the magnetic moment of magnetic nanoparticles by employing deep-learning algorithms. In the reconstructed magnetic images, the expression intensity of the biomarkers was quantified with the absolute magnetic signal. The IMM has excellent signal stability, and the magnetic signal in our samples had not changed after more than 1.5 y under ambient conditions. Furthermore, we realized multimodal imaging of tumor tissues by combining IMM with hematoxylin-eosin staining, immunohistochemistry, or immunofluorescence microscopy in the same tissue section. Overall, our study provides a different histological method for both molecular mechanism research and accurate diagnosis of human cancer.

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy.

The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.

TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity.

The maturation process of NK cells determines their functionality during which IL-15 plays a critical role. However, very few checkpoints specifically targeting this process have been discovered. Here, we report that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in both mice and humans. NK-specific TIPE2 deficiency increased mature NK cells in mice, and these TIPE2-deficient NK cells exhibited enhanced activation, cytotoxicity, and IFN-γ production upon stimulation and enhanced response to IL-15 for maturation. Moreover, TIPE2 suppressed IL-15­triggered mTOR activity in both human and murine NK cells. Consequently, blocking mTOR constrained the effect of TIPE2 deficiency on NK cell maturation in response to IL-15. Last, NK-specific TIPE2-deficient mice were resistant to tumor growth in vivo. Our results uncover a potent checkpoint in NK cell maturation and antitumor immunity in both mice and humans, suggesting a promising approach of targeting TIPE2 for NK cell­based immunotherapies.

Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients.

Unrelated cord blood transplantation (UCBT) is an effective treatment for hematopoietic disorders. However, this attractive approach is frequently accompanied by pre-engraftment syndrome (PES), severe cases of PES are associated with enhanced mortality and morbidity, but the pathogenesis of PES remains unclear. Here we show that GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and that monocytes are the main source of IL-6 during PES. Further, we report the outcome of a single arm, single-center clinical study of tocilizumab in the treatment of steroid-refractory severe PES patients (www.chictr.org.cn ChiCTR1800015472). The study met the primary outcome measure since none of the patients was nonrelapse death during the 100 days follow-up. The study also met key secondary outcomes measures of neutrophil engraftment and hematopoiesis. These findings offer a therapeutic strategy with which to tackle PES and improve nonrelapse mortality.

Rapamycin Pretreatment Rescues the Bone Marrow AML Cell Elimination Capacity of CAR-T Cells.

PURPOSE: Ongoing clinical trials show limited efficacy for Chimeric antigen receptor (CAR) T treatment for acute myeloid leukemia (AML). The aim of this study was to identify potential causes of the reported limited efficacy from CAR-T therapies against AML. EXPERIMENTAL DESIGN: We generated CAR-T cells targeting Epithelial cell adhesion molecule (EpCAM) and evaluated their killing activity against AML cells. We examined the impacts of modulating mTORC1 and mTORC2 signaling in CAR-T cells in terms of CXCR4 levels. We examined the effects of a rapamycin pretreatment of EpCAM CAR-T cells (during ex vivo expansion) and assessed the in vivo antitumor efficacy of rapamycin-pretreated EpCAM CAR-T cells (including CXCR4 knockdown cells) and CD33 CAR-T cells in leukemia xenograft mouse models. RESULTS: EpCAM CAR-T exhibited killing activity against AML cells but failed to eliminate AML cells in bone marrow. Subsequent investigations revealed that aberrantly activated mTORC1 signaling in CAR-T cells results in decreased bone marrow infiltration and decreased the levels of the rapamycin target CXCR4. Attenuating mTORC1 activity with the rapamycin pretreatment increased the capacity of CAR-T cells to infiltrate bone marrow and enhanced the extent of bone marrow AML cell elimination in leukemia xenograft mouse models. CXCR4 knockdown experiments showed that CXCR4 contributes to the enhanced bone marrow infiltration capacity of EpCAM CAR-T cells and the observed reduction in bone marrow AML cells. CONCLUSIONS: Our study reveals a potential cause for the limited efficacy of CAR-T reported from current AML clinical trials and illustrates an easy-to-implement pretreatment strategy, which enhances the anti-AML efficacy of CAR-T cells.See related commentary by Maiti and Daver, p. 5739.

Organ-Specific Immune-Related Adverse Events for PD-1 Antibodies in Lung Cancer Treatment.

Anti-PD-1 therapy has revolutionized the clinical treatment of lung cancer. With the increasing number of lung cancer patients being treated, there is also an increase in the number of immune-related adverse events (irAEs) being reported. These irAEs involve multiple organs and systems, mainly manifest as inflammatory side effects, and are different from the adverse events observed with traditional lung cancer treatment. These effects are often mild and treatable and reversible; however, in a few cases the side effects can be severe and lead to termination of immunotherapy. Management involves glucocorticoid-based related immunomodulators, which should be carefully prescribed to balance the efficacy and side effects of the PD-1 antibody treatment. This review will describe the characteristics and mechanisms of irAEs in specific organs, and will serve as a guide to help optimize treatment plans and improve patient outcomes.