Immune-mediated Effects Research Articles

Abstract 4995: Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer

Abstract Metastasis-ablative radiotherapy is a new therapeutic approach that prolongs survival in patients with advanced cancers. Tumour irradiation can elicit an immunogenic cell death resulting in the expansion of tumour-reactive T cells and eradication of both irradiated and distant non-irradiated metastases, referred to as the “abscopal effect”. This abscopal response, nevertheless, is observed in a minority of patients suggesting uncharacterized mechanisms that prevent robust systemic anti-tumor immune response. Tumour-derived extracellular vesicles (TdEVs) have recently emerged as mediators of antitumor immunity but their immunomodulatory role in response to radiotherapy remains largely unknown. Recent clinical studies by our lab have demonstrated that circulating levels of tumour-derived extracellular vesicles (tdEVs) are elevated in response to radiotherapy and high tdEV concentrations are associated with reduced levels of peripheral cytotoxic CD8+ T cells and higher risk of disease recurrence in advanced prostate cancer. Based on our findings, we hypothesize that radiotherapy induces the release of tumor-derived EVs that suppress anti-tumor immunity. Prostate cancer cells (PC3 and DU145) were irradiated with clinically used doses of ionizing radiation (20Gy x 1 or 10Gy x 3 fractions) and tdEVs were co-cultured with human CD8+ T cells to measure their proliferation and cytotoxic activity. Increased levels of tdEVs were released by tumour cells treated with radiotherapy. A higher frequency of impaired T cell cytotoxic activity and a reduction in CD8 T cell proliferation was found in the 10Gy x 3 radiation regimen. Proteomic analysis and western blot showed an increased expression of the immune checkpoint molecule B7-H3 on the tumour cell surface and tdEVs in response to radiotherapy. While coculture of CD8 T cells with B7-H3 depleted tdEVs led to recovery of T-cell cytotoxic ability, overexpression of the B7-H3 in tdEVs inhibited cytotoxic activity. This study provides a rationale for future studies in which we will test the immune-mediated effects of radiotherapy-induced tdEVs in immunocompetent mouse models and investigate B7-H3 blockade as a therapeutic approach to boost abscopal response in the treatment of advanced prostate cancer. Citation Format: Chisom J. Uzendu, Yohan Kim, Roxane R. Lavoie, Haidong Dong, Sean Park, Fabrice Lucien-Matteoni. Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4995.

Panaxynol improves crypt and mucosal architecture, suppresses colitis-enriched microbes, and alters the immune response to mitigate colitis.

Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly (P < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (P < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). In addition, panaxynol significantly (P < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.NEW & NOTEWORTHY In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as asafe and effective treatment option for colitis patients.

Effectiveness of Rhenium(I)-diselenoether Low Doses in a Triple-negative Breast Cancer Chicken Embryo Model.

Rhenium(I)-diselenoether (Re-diSe) is a promising anticancer agent composed of one rhenium and two selenium atoms. Its effectiveness was established in inhibiting cancer cells while maintaining low toxicity toward normal cells at a 5 μM dose for 120 hours in MDA-MB-231 cells. In MDA-MB-231 breast tumor-bearing mice, anti-tumor and anti-metastatic effects were observed at a 10 mg/kg dose. However, contradictory results were observed in the 4T1 breast cancer model, where a dose of 60 mg/kg had a pro-tumor effect. To address these discrepancies, the efficacy of Re-diSe at the effective 10 mg/kg dose was validated in a transplanted MDA-MB-231 breast tumor model using the chicken chorioallantoic membrane assay. MDA-MB-231 cancer cells were xenografted onto the chicken chorioallantoic membrane (CAM), and daily drug administration was carried out for nine days at doses of 0.1, 1, and 10 mg/kg. At the study's conclusion, a standard histological analysis was conducted. The low dose of 0.1 mg/kg showed a significant reduction in tumor weights compared to controls. The 1 mg/kg dose resulted in an increased inflammation score but did not induce a significant difference in tumor weights compared to the 0.1 mg/kg dose. Notably, at the 10 mg/kg dose, six out of 11 treated embryos displayed no visible signs of tumors. These tumors exhibited extensive tumor necrosis and significant infiltration by inflammatory cells. In this particular model, the anticancer efficacy of Re-diSe was achieved at the low dose of 0.1 mg/kg. The higher dose of 10 mg/kg, while eliminating visible tumors, might have immune-mediated effects, as indicated by substantial tumor necrosis and infiltration by inflammatory cells. Overall, this study successfully demonstrated the effectiveness of Re-diSe as an anticancer agent.

Paraneoplastic Neurological Syndromes as Initial Presentation of Tumors: An Eight-Year Single-Center Experience

Background: Paraneoplastic Neurological Syndromes (PNS) comprise a diverse group of disorders propagated by immune-mediated effects of malignant tumors on neural tissue. Methods: A single-center longitudinal study was performed including consecutive adult patients treated at a tertiary academic hospital between 2015 and 2023 and diagnosed with PNS. PNS were ascertained using the 2004 and the revised 2021 PNS-Care diagnostic criteria. Results: Thirteen patients who fulfilled the 2004 definite PNS criteria were included. PNS comprise diverse neurological syndromes, with neuromuscular junction disorders (54%) and limbic encephalitis (31%) being predominant. PNS-related antibodies were detected in 85% of cases, including anti-AChR (n = 4), anti-P/Q-VGCC (n = 3), anti-Hu (n = 3), anti-Yo (n = 1), anti-Ma (n = 1), anti-titin (n = 1), anti-IgLON5 (n = 1), and anti-GAD65 (n = 1). Thymoma (31%), small-cell lung cancer (23%), and papillary thyroid carcinoma (18%) were the most frequent tumors. Imaging abnormalities were evident in 33% of cases. Early immunotherapy within 4-weeks from symptom onset was associated with favorable outcomes. At a mean follow-up of 2 ± 1 years, two patients with anti-Hu and anti-Yo antibodies died (18%). Four and three patients fulfilled the 2021 PNS-Care diagnostic criteria for definite and probable PNS, respectively. Conclusions: This study highlights the clinical heterogeneity of PNS, emphasizing the need for early suspicion and prompt treatment initiation for optimal outcomes.

Glucans and heteroglycans of fungi and their possibilities in immunotherapy of malignant neoplasms

The present review is devoted to the oncostatic properties of glucans and heteroglycans produced by higher fungi. These are the most pharmacologically promising substances, since they are produced in large quantities both by artificially grown mycelium and fruiting bodies, do not require complex purification methods, are devoid of toxicity, and, having a complex (immune-mediated and direct) effect on tumors, do not require any complex fractionation procedures. The diversity of β-glucans produced by fungi is shown, the main types of these macromolecules are considered (according to the structural features of the macromolecule, the linear and branched forms of β-glucans are distinguished, first of all). Heteroglycans, a more diverse but less studied group of fungal compounds, have also been characterized. The effects of fungal polysaccharides and heteroglycans on immune and cancer cells described in the literature are considered. The long and branched chains of these biopolymers, as well as peptides and lipids covalently bound to them, have fragments that are complementary to the binding sites of the surface receptors of the animal cell and thus act as their agonists or antagonists. They are recognized by the receptors of antigen-representing cells of the immune system as pathogen-associated molecular patterns, what leads to the activation of the cytotoxic component of the immune system; to reduce their tolerogenic and immunosuppressive signaling. Prospects for further study of fungal glucans and heteroglycans are outlined.

Updates in the Management of Paraneoplastic Syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS.

Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor-infiltrating lymphocytes in an experimental carcinoma model

Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types. Interest in repurposing metformin to treat cancer has not been translated into encouraging clinical benefit. In animal models, metformin activated cytotoxic T cells and exerted an immune-mediated anticancer effect. The current research was conducted to investigate the possible therapeutic benefit of metformin in combination with metronomic cyclophosphamide in an experimental cancer model. Ehrlich ascites carcinoma was injected into the subcutaneous tissue to induce solid tumors in syngeneic mice. Exponential solid tumor growth ensued and was effectively arrested with the administration of a cytotoxic dose of parenteral cyclophosphamide. Alternatively, oral metformin and continuous, low-dose cyclophosphamide significantly inhibited tumor growth relative to untreated mice. The drug combination was well tolerated. Histopathological examination of the tumor showed an increased number of tumor-infiltrating lymphocytes and enhanced expression of granzyme B by this drug combination. The current data suggests a potential role of metformin and metronomic chemotherapy that warrants further investigation.

Flow cytometry vs conventional methods for the evaluation of anti-PF4/heparin antibodies:a single center study.

Aim: Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening, immune-mediated adverse effect of heparin administration. This study compares frequently used laboratory assays in terms of their effectiveness in HIT diagnosis.Materials & methods: Fifty patients with suspected HIT were tested by gel immunoassay and solid phase PF4/heparin antibody ELISA. On positive results, platelet activation markers P-selectin and Annexin V were assayed using flow cytometry.Results: Thirty/50 patients were negative for both immunoassays. Flow cytometry was performed in the 20 immunoassay positive patients. Platelet activation was observed in 7/20 in the presence of low heparin concentration (0.2IU/ml).Conclusion: The results are in accordance with the currently available literature and flow cytometry seems a promising alternative in HIT laboratory investigation.

Development and validation of a nomogram model for predicting the risk of venous thromboembolism in lymphoma patients undergoing chemotherapy: a prospective cohort study conducted in China

Background The mechanism of Venous thromboembolism (VTE) is complicated and difficult to prevent due to factors such as bone marrow invasion, therapy, and immune-mediated effects. This study aims to establish a nomogram model for predicting the risk of thrombosis in lymphoma patients undergoing chemotherapy, which has been increasing over the past 30 years. Methods The data of lymphoma patients from the Affiliated Cancer Hospital of Chongqing University in China between 2018 and 2020 were analyzed. This included age, sex, body mass index, ECOG score, histological type, Ann Arbour Stage, white blood cells count, haemoglobin level, platelet count, D-dimer level, and chemotherapy cycle. Univariate and multivariate cox analysis was used to determine the risk factors for VTE. Characteristic variables were selected to construct a nomogram model which was then evaluated using ROC curve and calibration. Results Age, sex, PLT, D-dimer and chemotherapy cycle were considered as independent influencing factors of VTE. The mean (standard deviation) of the C index, AUC and Royston D statistics of 1000 cross-validations of the Nomogram model were 0.78 (0.01), 0.81 (0.01) and 1.61(0.07), respectively. It indicates a good calibration degree and applicability value as shown by the calibration curve. The DCA curve showed a rough threshold range of 0.05–0.60 with a good model. Conclusions We have established and validated a nomogram model for predicting the risk of thrombosis in lymphoma patients. This model can assess the risk of thrombosis in each individual patient, enabling the identification of high-risk groups and targeted preventive treatment.

Synergistic Immune-Mediated Anti-tumour Effect of Dostarlimab and Radiotherapy in the Management of MSI-H/dMMR Endometrial Cancer: A Case Report

Endometrial carcinoma (EC) is the world’s most common gynaecological malignancy and the fourth most common carcinoma in females. Microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) EC is the most represented EC subtype and is strongly associated with higher expression of anti-programmed death 1 (PD-1) receptor levels, potentially making these tumours responsive to anti-PD-1 treatment. This case report describes the screening and treatment strategies of a 67-year-old female diagnosed with EC, which was initially treated with adjuvant therapy with chemotherapy and radiotherapy (RT). However, after the emergence of a secondary tumour lesion in the brain and other secondary body lesions, the patient started dostarlimab therapy (an anti-PD-1 monoclonal antibody) combined with RT, to evaluate a possible synergistic immune-mediated anti-tumour effect. After 5 months of therapy, the instrumental follow-up showed a complete brain lesion response, and 5 months later, a partial response of the body lesions too. In conclusion, this case report outcome supports the combination of RT and immunotherapy to control and manage MSI-H/dMMR ECs.

Transcriptional Heterogeneity and Clonal Evolution between Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia

Clonal evolution of leukemia is driven by different selection pressures operating on a heterogeneous population of cells. These pressures may include therapy-induced and immune-mediated effects which eradicate the majority of cells, but which simultaneously provide a selective advantage to a minor population of cells that is genetically or transcriptionally distinct and which grow out towards relapse. We integrated single-cell RNA-seq, DNA-seq, ATAC-seq and long-read Oxford Nanopore sequencing of matched diagnosis and relapse samples of 20 pediatric AML patients with various genetic driver mutations representative of the mutational spectrum to map the genetic and transcriptional evolution of these cancers (Figure 1). We investigated whether and how differences in AML-initiating mutations impact on transcriptional programs in AML blasts and their surrounding microenvironmental cells and how the mutational and transcriptional features of these cells are impacted by cancer therapy. Specifically, we traced the progression of these traits from the point of diagnosis to the occurrence of relapse. Our single cell RNA and ATAC data showed high patient-to-patient heterogeneity, with gene expression patterns that were largely conserved between diagnosis and relapse. Analyses of the differentially expressed genes and factorization into “metaprograms” revealed gene sets that were shared between relapse samples but could not be tied to interpretable common “biological signatures”. Exome-seq revealed highly significant changes in somatic variants, most notably in members of the RAS-signaling pathway (i.e., KRAS, NRAS, PTPN11, NF1 and CBL). Interestingly, pathogenic RAS mutations were often gained, but also lost, or switched between different RAS-pathway members, indicating that RAS-mutations are associated with extensive clonal evolution/rewiring. To unveil the effect of accumulation or loss of (sub)clones with RAS mutations on the transcriptional phenotype and epigenetic landscape of leukemic blasts, we performed targeted screening of somatic variants at single-cell resolution. To this aim, we combined long-read nanopore sequencing with 10x Genomics single-cell technologies, enabling us to directly link genetic, transcriptomics and epigenetic changes in distinct (sub)clones. Taken together, we successfully reconstructed patient-specific genetic and transcriptional evolutionary trajectories in pediatric AML. This knowledge will be essential for our understanding of AML relapse and therapy resistance.

Impact of Typical and Atypical Complex Karyotype Subgroups on Outcome of AML Patients Undergoing Allogeneic Stem Cell Transplantation

Introduction Acute myeloid leukemia (AML) with a complex karyotype (CKT) confers an adverse prognosis, even within the subgroup of patients (pts) with adverse risk according to European LeukemiaNet 2022 (ELN22) risk stratification. Mrózek et al. further characterized CKT pts according to distinct mechanisms of leukemogenesis into balanced (presence of ≥1 balanced rearrangement), and unbalanced CKT (CKT ub, exclusively unbalanced cytogenetic abnormalities). Considering the high incidence of deletions (del) of 5q, 7q, and 17p in CKT, CKT ub were further divided in typical CKT ub (with latter abnormalities present), and atypical CKT ub (with exclusively other abnormalities). In the context of consolidating chemotherapy, typical CKT ub was associated with shorter event-free survival (EFS) and overall survival (OS) compared to atypical CKT ub. However, we lack data in the context of allogeneic hematopoietic stem cell transplantation (HSCT) which remains the preferred treatment in eligible pts. Here we aimed to investigate this classification in CKT AML pts consolidated by HSCT. Methods We analyzed 263 pts with AML who were classified as ELN22 adverse risk and underwent an allogeneic HSCT. 105 had a CKT, while 158 fulfilled other ELN22 adverse risk criteria. Of the pts harboring a CKT, median age at HSCT was 61 (range 20 - 76) years. Remission status at HSCT was first complete remission with or without count recovery (CR/CRi, 62%) or refractory AML (38%). Conditioning intensity according to EBMT criteria were myeloablative (19%), reduced intensity (31%) or non-myeloablative (50%). Donors were matched related (16%), haploidentical (2%) or matched (65%) or mismatch unrelated (17%).Cytogenetic analyses at diagnosis were performed using standard techniques of banding and in situ hybridization. Pretreatment genomic DNA was screened for genes recurrently mutated in myeloid malignancies using next generation sequencing. Median follow-up alive was 1.3 years. Results Pts with a CKT had a significantly shorter EFS ( P&amp;lt;.01) and OS ( P&amp;lt;.01) than other ELN22 adverse risk pts. Of all pts harboring a CKT, 17% had a balanced CKT, and 83% a CKT ub. Among CKT ub, 85% were classified as typical (67% with del(5q), 49% with del(7q), 26% with del(17p), Figure 1). Comparing typical and atypical CKT ub, pts with typical CKT ub more often had a monosomal karyotype ( P&amp;lt;.01), had more cytogenetic abnormalities (in typical CKT ub median 8 [range 3-39] vs atypical CKT ub median 6 [range 3-9], P=.04), more often TP53 mutations ( P=.02), less often RUNX1 mutations ( P=.03) and a lower LDH at diagnosis ( P=.03). They also had a higher expression of the leukemic stem cell markers CD34+/CD38- ( P=.01) and GPR56 ( P&amp;lt;.01). However, after allogeneic HSCT, EFS ( P=.50) and OS ( P=.50) did not differ between pts with typical and atypical CKT ub (Figure 2). Next, we looked for other adverse prognostic factors within CKT pts receiving HSCT, which in univariate analyses were the presence of a del(5q) (EFS P&amp;lt;.01 and OS P=.03), a del(17p) (EFS P=.10 and OS P=.02), the presence of ≥5 vs &amp;lt;5 cytogenetic aberrations (EFS P=.03 and OS P=.06), a concomitant TP53 mutation (EFS P=.01 and OS P=.01), and a higher age at HSCT (≥60 years, EFS P=.04 and OS P=.08). In contrast, neither the presence of a del(7q) nor a monosomal karyotype impacted EFS or OS within pts with a CKT. In multivariate analyses for CKT pts, the presence of ≥ 5 cytogenetic aberrations (Hazard Ratio. [HR] 1.7, 95% Confidence Interval [CI] 1.0-3.0, P=.05), higher age at HSCT (HR 1.6, 95% Ci 1.1-2.5, P=.02), and no CR/CRi at HSCT (HR 1.7, 95% CI 1.1-2.7, P=.01) were adverse factors for EFS, while the presence of a del(17p) (HR 2.0, 95% CI 1.2-3.4, P=.01), higher age at HSCT (HR 1.8, 95% CI 1.1-3.0, P=.02), and no CR/CRi at HSCT (HR 1.8, 95% CI 1.1-2.9, P=.02) were adverse factors for OS. Conclusion The presence of a CKT retains its negative prognostic impact after HSCT and differentiates within the ELN22 adverse risk group. However, in contrast to chemotherapy consolidation alone, the subgroup of pts harboring a typical CKT ub did not perform worse than pts with an atypical CKT ub, indicating a potential immune-mediated beneficial effect of HSCT. Within pts with a CKT receiving HSCT, we identified additional prognostic factors including the presence of ≥5 cytogenetic aberrations. These pts are in urgent need for novel post HSCT approaches.

Proenkephalin deletion in hematopoietic cells induces intestinal barrier failure resulting in clinical feature similarities with irritable bowel syndrome in mice

Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer’s patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.

Bioactivable STING Nanoagonists to Synergize NIR-II Mild Photothermal Therapy Primed Robust and Long-Term Anticancer Immunity.

Pharmacological activation of the stimulator of interferon genes (STING) pathway has become a promising strategy for cancer immunotherapy. However, the insufficient tumorous accumulation, rapid clearance, and short duration of drug efficacy in the tumor microenvironment of small structural STING agonists greatly compromise the therapeutic efficacy. Herein, a tumorous extracellular matrix (ECM) is presented anchoring STING agonist-based photoimmunothernostic nanomedicine (SAPTN) that can be activated by mild-temperature photothermal therapy (mild PTT) induced neutrophilic inflammation. The SAPTN owns second window near-infrared (NIR-II) photonics properties fitting for NIR-II fluorescence and photoacoustic imaging-guided cancer therapy. The aggregates SAPTN targeting to the ECM provide slow and continuous release of potent STING agonists diABZIs. The mild PTT and long-lasting STING agonists released in the ECM synergisticallyprime systematic, robust, and long-term anticancer immunity. In a tumor model, this approach leads to complete tumor eradication in about 100% of mice with orthotopic breast tumors, and the mice regained tumor-free survival of at least 2 months. In addition, the immune-mediated abscopal effect shows inhibition of the distant solid tumor growth by intratumoral administration of SAPTN with laser irradiation. Overall, this approach represents a generalized photoactivable nanomedicine to prime anticancer immunity for improved cancer theranostics.

Prolonged haematologic toxicity in CAR-T-cell therapy: A review.

Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies. In this review, we provide a narrative of PHT occurring in patients following CAR-T-cell therapy; evidence of PHT treatment strategies is also presented, with the aim of contributing to systematic understanding of PHT.

Interferon signaling restrains renal cell carcinoma heterogeneity

Type I interferon (IFN) is central to cancer surveillance as it mediates both direct and immune-mediated oncosuppressive effects. A recent study by Perelli et al. suggests that the ability of renal cancer cells to tolerate complex karyotypic alterations elicited by chromosomal instability (CIN), and ultimately acquire full metastatic potential, is also negatively regulated by IFN signaling.

Emergencies in cancer immunotherapy

Immunomodulatory therapies are becoming increasingly important in uro-oncology. For this reason, we will probably be increasingly confronted with side effects. In addition, there is an increasing number of combinations with other mechanisms of action. Immune-mediated side effects may occur as a consequence of this therapy. These are different from the side effects of chemotherapy and other targeted therapies and therefore require different treatment strategies. Based on the current literature, the data on graduation and stage-dependent management will be presented as well as illustrated with examples from practice. Literature review on the detection and therapeutic management of adverse events mediated in the setting of immuno-oncologic therapy. Treatment-related events can in principle affect all organ systems. Toxicities in the area of the skin, such as rash or pruritus, hypo- or hyperthyreosis, arthritis, muscle pain and gastrointestinal symptoms are frequently seen. In terms of frequency, most side effects are grade 1 to 2, but grade 3 to 4 toxicities are also generally well treatable if detected early. Rare complications such as neurological toxicities, pneumonitis or carditis can develop a fulminant course if diagnosed too late. Even emergencies are manageable if we know the most important side effects and the therapeutic options. Immune-mediated side effects are of particular importance because they can affect any organ system. However, as long as we consider the possibility of toxicity from checkpoint inhibitors when the patient presents with symptoms, most side effects are easy to treat and therefore manageable.

Exercise as an Immune Boost: Mechanism-Driven Support for Lifestyle Interventions.

Modifiable host factors have demonstrated promise to enhance responses to immunotherapy. In this issue, Savage et al. investigated the use of aerobic exercise to enhance antitumor immunity in a murine model of melanoma. They show that treadmill running improves tumor vasculature and alters both T-cell and myeloid-cell infiltration of the tumor via an ERK5-dependent mechanism, adding to the growing evidence supporting the immune-mediated antitumor effects of exercise. See related article by Savage et al., p. 1168 (3).

T Cell-intrinsic Immunomodulatory Effects of TAK-981 (Subasumstat), a SUMO-activating Enzyme Inhibitor, in Chronic Lymphocytic Leukemia.

Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T-cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small-molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I IFN response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases regulatory T cell (Treg) differentiation and enhances secretion of IFNγ by CD4+ and CD8+ T cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T-cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematologic malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8+ T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.

CTLA4 DNA methylation is associated with CTLA-4 expression and predicts response to immunotherapy in head and neck squamous cell carcinoma

BackgroundThe majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value.MethodsWe analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine.ResultsLower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines.ConclusionsOur results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.