Integrated MRI–Immune–Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

Simple Summary: Despite crucial scientific advances, Glioblastoma (GB) remains a fatal disease with limited therapeutic options and a lack of suitable biomarkers. The unveiled competence of the brain immune system together with the breakthrough advent of immunotherapy has shifted the present translational research on GB towards an immune-focused perspective. Several clinical trials targeting the immunosuppressive GB background are ongoing. So far, results are inconclusive, underpinning our partial understanding of the complex cancer-immune interplay in brain tumors. High throughput Magnetic Resonance (MR) imaging has shown the potential to decipher GB heterogeneity, including pathologic and genomic clues. However, whether distinct GB immune contextures can be deciphered at an imaging scale is still elusive, leaving unattained the non-invasive achievement of prognostic and predictive biomarkers. Along these lines, we integrated genetic, immunopathologic and imaging features in a series of GB patients. Our results suggest that multiparametric approaches might offer new efficient risk stratification models, opening the possibility to intercept the critical events implicated in the dismal prognosis of GB. Abstract: Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two- Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0–47.37) in patients displaying 0–1 risk factor and 13 months (95% CI 7.22–19.22) in the presence of 2–3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26–9.09). Conclusion: Interlacing MRI–immune–genetic features may provide highly significant risk-stratification models in GB patients

Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC

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Exploring genetic and immune underpinnings of the sexual dimorphism in tumor response to immune checkpoints inhibitors: A narrative review

Introduction In spite of the undisputed relevance of sex as critical biologic variable of the immune landscape, still limited is our understanding of the basic mechanisms implicated in sex-biased immune response thereby conditioning the therapeutic outcome in cancer patients. This hindrance delays the actual attempts to decipher the heterogeneity of cancer and its immune surveillance, further digressing the achievement of predictive biomarkers in the current immunotherapy-driven scenario. Body: The present review concisely reports on genetic, chromosomal, hormonal, and immune features underlying sex-differences in the response to immune checkpoint inhibitors (ICIs). In addition to outline the need of robust data on ICI pharmaco-kinetics/dynamics, our survey might provide new insights on sex determinants of ICI efficacy and suggests uncovered pathways that warrant prospective investigations. Conclusion According to a sharable view, we propose to widely include sex among the co-variates when assessing the clinical response to ICI in cancer patients

Can we identify a preferred first-line strategy for sarcomatoid renal cell carcinoma? A network meta-analysis

Background: Combinations based on immune checkpoint inhibitors are the new first-line standard treatment for metastatic renal cell carcinoma. Sarcomatoid renal cell carcinoma (sRCC) has a dismal prognosis but good immunogenicity. Methods: The authors performed a network meta-analysis of Phase III randomized trials of immune checkpoint inhibitor-based combinations versus standard tyrosine kinase inhibitor monotherapy reporting data for sRCC. The endpoints were overall survival, progression-free survival and objective response rate. Results: Five trials comprising 569 sRCC patients (out of a total of 4409 metastatic renal cell carcinoma patients) were included. Nivolumab-cabozantinib was the highest ranking treatment for overall survival (p-value = 88%) and progression-free survival (p-value = 81%). Atezolizumab-bevacizumab had the highest rank for objective response rate (p-value = 80%). Conclusion: Despite some limitations, nivolumab-cabozantinib might be the preferred first-line option for sRCC in terms of efficacy

Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular Entity and a Clinical Challenge in the Current Therapeutic Scenario

: Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary tract UC (UTUC). BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment

Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer

Immunotherapy has prompted a paradigm shift in advanced non-small cell lung cancer (NSCLC) treatment, by demonstrating superior efficacy to chemotherapy alone both in second- and in first-line setting. Novel insights on molecular mechanisms and regimens to enhance the efficacy of immunotherapy are warranted, as only a minority of patients (˜20%) respond to checkpoint blockade. Taking into account the multiple mechanisms adopted by tumor cells to evade the immune system through cancer immunoediting, the frontline combination of immune checkpoint inhibitors with chemotherapy appears to be a successful strategy as: 1) it enhances the recognition and elimination of tumor cells by the host immune system (immunogenic cell-death), and 2) it reduces the immunosuppressive tumor microenvironment. Remarkably, the immune checkpoint inhibitors pembrolizumab and atezolizumab have already been approved by the FDA in combination with chemotherapy for the first-line treatment of advanced NSCLC and many other chemo-immunotherapeutic regimens have been evaluated as an initial therapeutic approach in metastatic NSCLC. Concurrently, several preclinical studies are evaluating the molecular mechanisms underlying immunomodulation by conventional chemotherapeutic agents (platinum salts, antimitotic agents, antimetabolites and anthracyclines), unraveling drug- and dose/schedule-dependent effects on the immune system that should be exploited to achieve synergistic clinical activity. The current review provides a detailed overview of the immunobiological rationale and molecular basis for combining immune checkpoint inhibitors with chemotherapy for the treatment of advanced NSCLC. Moreover, current evidence and future perspectives towards a better selection of patients who are more likely to benefit from chemo-immunotherapy combinations are discussed

The radiological appearances of lung cancer treated with immunotherapy: a review

Therapy and prognosis of several solid and hematologic malignancies, including non-small cell lung cancer (NSCLC), have been favourably impacted by the introduction of immune checkpoint inhibitors (ICIs). Their mechanism of action relies on the principle that some cancers can evade immune surveillance by expressing surface inhibitor molecules, known as "immune checkpoints". ICIs aim to conceal tumoral checkpoints on the cell surface and reinvigorate the ability of the host immune system to recognize tumour cells, triggering an antitumoral immune response.In this review, we will focus on the imaging patterns of different responses occurring in patients treated by ICIs. We will also discuss imaging findings of immune-related adverse events (irAEs), along with current and future perspectives of metabolic imaging. Finally, we will explore the role of radiomics in the setting of ICI-treated patients

Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences

Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and RORα are overexpressed in RCC tissues and correlate with patients’ prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1α (HIF-1α) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-α, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications