Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response. SIGNIFICANCE: Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma.

Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.

The Impact of Extent of Ablation on Survival of Patients With Newly Diagnosed Glioblastoma Treated With Laser Interstitial Thermal Therapy: A Large Single-Institutional Cohort.

BACKGROUND: Upfront laser interstitial thermal therapy (LITT) can be used as part of the treatment paradigm in difficult-to-access newly diagnosed glioblastoma multiforme (ndGBM) cases. The extent of ablation, though, is not routinely quantified; thus, its specific effect on patients' oncological outcomes is unclear. OBJECTIVE: To methodically measure the extent of ablation in the cohort of patients with ndGBM and its effect, and other treatment-related parameters, on patients' progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective study was conducted on 56 isocitrate dehydrogenase 1/2 wild-type patients with ndGBM treated with upfront LITT between 2011 and 2021. Patient data including demographics, oncological course, and LITT-associated parameters were analyzed. RESULTS: Patient median age was 62.3 years (31-84), and the median follow-up duration was 11.4 months. As expected, the subgroup of patients receiving full chemoradiation was found to have the most beneficial PFS and OS (n = 34). Further analysis showed that 10 of them underwent near-total ablation and had a significantly improved PFS (10.3 months) and OS (22.7 months). Notably, 84% excess ablation was detected which was not related to a higher rate of neurological deficits. Tumor volume was also found to influence PFS and OS, but it was not possible to further corroborate this finding because of low numbers. CONCLUSION: This study presents data analysis of the largest series of ndGBM treated with upfront LITT. Near-total ablation was shown to significantly benefit patients' PFS and OS. Importantly, it was shown to be safe, even in cases of excess ablation and therefore could be considered when using this modality to treat ndGBM.

Spatial immunosampling of MRI-defined glioblastoma regions reveals immunologic fingerprint of non-contrast enhancing, infiltrative tumor margins.

Glioblastoma (GBM) treatment includes maximal safe resection of the core and MRI contrast-enhancing (CE) tumor. Complete resection of the infiltrative non-contrast-enhancing (NCE) tumor rim is rarely achieved. We established a safe, semi-automated workflow for spatially-registered sampling of MRI-defined GBM regions in 19 patients with downstream analysis and biobanking, enabling studies of NCE, wherefrom recurrence/progression typically occurs. Immunophenotyping revealed underrepresentation of myeloid cell subsets and CD8+ T cells in the NCE. While NCE T cells phenotypically and functionally resembled those in matching CE tumor, subsets of activated (CD69hi) effector memory CD8+ T cells were overrepresented. Contrarily, CD25hi Tregs and other subsets were underrepresented. Overall, our study demonstrated that MRI-guided, spatially-registered, intraoperative immunosampling is feasible as part of routine GBM surgery. Further elucidation of the shared and spatially distinct microenvironmental biology of GBM will enable development of therapeutic approaches targeting the NCE infiltrative tumor to decrease GBM recurrence.

Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.

In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin ß1 and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an enhanced cell adhesion signature. Integrin ß1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, whereas treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin ß1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM. SIGNIFICANCE: Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth.

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases.

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

Tumor Treating Fields: killing two birds with one stone.

Given its aggressive natural history and immunosuppressive nature, glioblastoma (GBM) remains difficult to treat. Tumor Treating Fields (TTFields) are a promising treatment for GBM patients, yet the entirety of their antitumor action has not been fully elucidated. In a recent issue of the JCI, Chen et al. explored the effect of TTFields in reinvigorating immune responses. By elegant step-by-step approaches, the authors demonstrated that TTFields promote the production of immune-stimulating proinflammatory and interferon type 1 cytokines in tumor cells in a cGAS/STING- and AIM2 inflammasome-dependent mechanism, thereby activating the immune system. The findings show that TTFields not only directly inhibit tumor cell growth, as previously reported, but enhance antitumor immunity, suggesting TTFields can be used as an immune-modulating approach in GBM.

Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis.

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. OBJECTIVE: To compare LITT vs medical management (MM) in the treatment of RN. METHODS: A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. RESULTS: Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). CONCLUSION: These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

Stereotactic Laser Ablation (SLA) followed by consolidation stereotactic radiosurgery (cSRS) as treatment for brain metastasis that recurred locally after initial radiosurgery (BMRS): a multi-institutional experience.

INTRODUCTION: The optimal treatment paradigm for brain metastasis that recurs locally after initial radiosurgery remains an area of active investigation. Here, we report outcomes for patients with BMRS treated with stereotactic laser ablation (SLA, also known as laser interstitial thermal therapy, LITT) followed by consolidation radiosurgery. METHODS: Clinical outcomes of 20 patients with 21 histologically confirmed BMRS treated with SLA followed by consolidation SRS and > 6 months follow-up were collected retrospectively across three participating institutions. RESULTS: Consolidation SRS (5 Gy × 5 or 6 Gy × 5) was carried out 16-73 days (median of 26 days) post-SLA in patients with BMRS. There were no new neurological deficits after SLA/cSRS. While 3/21 (14.3%) patients suffered temporary Karnofsky Performance Score (KPS) decline after SLA, no KPS decline was observed after cSRS. There were no 30-day mortalities or wound complications. Two patients required re-admission within 30 days of cSRS (severe headache that resolved with steroid therapy (n = 1) and new onset seizure (n = 1)). With a median follow-up of 228 days (range: 178-1367 days), the local control rate at 6 and 12 months (LC6, LC12) was 100%. All showed diminished FLAIR volume surrounding the SLA/cSRS treated BMRS at the six-month follow-up; none of the patients required steroid for symptoms attributable to these BMRS. These results compare favorably to the available literature for repeat SRS or SLA-only treatment of BMRS. CONCLUSIONS: This multi-institutional experience supports further investigations of SLA/cSRS as a treatment strategy for BMRS.

Laser interstitial thermal therapy for brain metastases.

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment for intracranial lesions entailing thermal ablation via a stereotactically placed laser probe. In metastatic disease, it has shown the most promise in the treatment of radiographically progressive lesions after initial stereotactic radiosurgery, whether due to recurrent metastatic disease or radiation necrosis. LITT has been demonstrated to provide clinical benefit in both cases, as discussed in the review below. With its minimal surgical footprint and short recovery period, LITT is further advantaged for patients who are otherwise high-risk surgical candidates or with lesions in difficult to access locations. Exploration of the current data on its use in metastatic disease will allow for a better understanding of the indications, benefits, and future directions of LITT for these patients.

The Translocator Protein (TSPO) Genetic Polymorphism A147T Is Associated with Worse Survival in Male Glioblastoma Patients.

Glioblastoma (GBM) is the most common primary brain tumor in adults, with few available therapies and a five-year survival rate of 7.2%. Hence, strategies for improving GBM prognosis are urgently needed. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. High TSPO gene expression is associated with reduced survival in GBM patients; however, the relation between the most frequent TSPO genetic variant and GBM pathogenesis is not known. The present study retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. TSPO rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort of 441 patients. We observed similar trends in two other independent cohorts. These observations suggest that the TSPO rs6971 polymorphism could be a significant predictor of poor prognosis in GBM, with a potential for use as a prognosis biomarker in GBM patients. These results reveal for the first time a biological sex-specific relation between rs6971 TSPO polymorphism and GBM.

Late-week surgery and discharge to specialty care associated with higher costs and longer lengths of stay after elective lumbar laminectomy.

OBJECTIVE: In a healthcare landscape in which costs increasingly matter, the authors sought to distinguish among the clinical and nonclinical drivers of patient length of stay (LOS) in the hospital following elective lumbar laminectomy-a common spinal surgery that may be reimbursed using bundled payments-and to understand their relationships with patient outcomes and costs. METHODS: Patients ≥ 18 years of age undergoing laminectomy surgery for degenerative lumbar spinal stenosis within the Cleveland Clinic health system between March 1, 2016, and February 1, 2019, were included in this analysis. Generalized linear modeling was used to assess the relationships between the day of surgery, patient discharge disposition, and hospital LOS, while adjusting for underlying patient health risks and other nonclinical factors, including the hospital surgery site and health insurance. RESULTS: A total of 1359 eligible patients were included in the authors' analysis. The mean LOS ranged between 2.01 and 2.47 days for Monday and Friday cases, respectively. The LOS was also notably longer for patients who were ultimately discharged to a skilled nursing facility (SNF) or rehabilitation center. A prolonged LOS occurring later in the week was not associated with greater underlying health risks, yet it nevertheless resulted in greater costs of care: the average total surgical costs for lumbar laminectomy were 20% greater for Friday cases than for Monday cases, and 24% greater for late-week cases than for early-week cases ultimately transferred to SNFs or rehabilitation centers. A Poisson generalized linear model fit the data best and showed that the comorbidity burden, surgery at a tertiary care center versus a community hospital, and the incidence of any postoperative complication were associated with significantly longer hospital stays. Discharge to home healthcare, SNFs, or rehabilitation centers, and late-week surgery were significant nonclinical predictors of LOS prolongation, even after adjusting for underlying patient health risks and insurance, with LOSs that were, for instance, 1.55 and 1.61 times longer for patients undergoing their procedure on Thursday and Friday compared to Monday, respectively. CONCLUSIONS: Late-week surgeries are associated with a prolonged LOS, particularly when discharge is to an SNF or rehabilitation center. These findings point to opportunities to lower costs and improve outcomes associated with elective surgical care. Interventions to optimize surgical scheduling and perioperative care coordination could help reduce prolonged LOSs, lower costs, and, ultimately, give service line management personnel greater flexibility over how to use existing resources as they remain ahead of healthcare reforms.

Preclinical Modeling of Surgery and Steroid Therapy for Glioblastoma Reveals Changes in Immunophenotype that are Associated with Tumor Growth and Outcome.

PURPOSE: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment-including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment-has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined. EXPERIMENTAL DESIGN: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM. RESULTS: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles. CONCLUSIONS: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.

Immune suppression in gliomas.

INTRODUCTION: The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy. METHODS: We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body's immune system to evade detection and ensure tumor survival and proliferation. RESULTS: A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments. CONCLUSIONS: Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.

Stereotactic Laser Ablation of Glioblastoma.

The previous decade has seen an expansion in the use of laser interstitial thermal therapy (LITT) for a variety of pathologies. LITT has been used to treat both newly diagnosed and recurrent glioblastoma (GBM), especially in deep-seated, difficult-to-access lesions where open resection is otherwise infeasible or in patients who would not tolerate craniotomy. This review aims to describe the current state of the technology and operative technique, as well as summarize the outcomes data and future research regarding LITT as a treatment of GBM.

Neuro-Oncology Practice resources for optimizing care and practice in spinal oncology.

As the diagnosis and treatment of systemic cancers continues to improve, increased patient survival has resulted in a rise in the number of patients who develop spinal metastases (SM). Within many areas of oncology, utilization of multidisciplinary care models in the management and decision making of SM patients has proven effective for optimizing care and improving patient safety. Three main goals of an effective clinical pathway include improving outcomes and quality, improving the patient experience, and lowering cost. This paper outlines the strategies employed to optimally establish such a collaborative program for the management of patients with SM, as well as direct providers in and out of the field, patients and caregivers, and practice managers to the appropriate resources.

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.