NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.

CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.

T Cell Features in Glioblastoma May Guide Therapeutic Strategies to Overcome Microenvironment Immunosuppression.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-ß, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment.

Refining patient selection for next-generation immunotherapeutic early-phase clinical trials with a novel and externally validated prognostic nomogram.

Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.

Brain metastases and next-generation anticancer therapies: a survival guide for clinicians.

Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation.

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.

Highly specialized Breast Centers did not experience delay of care during COVID-19 pandemic in Italy: the Senonetwork experience.

AIM OF THE STUDY: The study aims to evaluate the performance of selected, high-volume, highly specialized, Italian Breast Centers at the time of COVID-19 pandemic (year 2020), compared to pre-pandemic time (year 2019), highlighting differences in terms of clinical presentation of breast cancer (BC) and therapeutic strategies. METHODS: Patients' data were provided by the Senonetwork data warehouse Senonet. In order to examine changes in the surgical and oncological management of BC patients during different phases of COVID-19 pandemic, we took advantage of a selection quality indicators (QIs). We performed the analyses in two time-frames, from July to September (Jul-Sep) (2019 versus 2020) and from October to December (Oct-Dec) (2019 versus 2020). RESULTS: Our analysis did not show any statistically significant difference in terms of diagnosis, surgical, oncological and radiation therapy procedures between the two trimesters 2019 and 2020. Nevertheless, we observed statistically significant differences, favoring 2020, when analyzing time-to surgery and time-to radiotherapy. On the other hand, we observed a significant reduction of neoadjuvant chemotherapy and we did not recollect any data on a major use of neoadjuvant endocrine therapy. CONCLUSIONS: In Italian Breast Centers, partners of Senonetwork, we could not observe any treatment delay or change in standard clinical practice for BC care during the 2020 pandemic year, compared to 2019 pre-pandemic year. This finding is in contrast with the globally reported decrease in the performance of the Italian Breast Centers due to the COVID-19 pandemic, and has to be linked to the sharp selection of Senonetwork Breast Centers.

Surgical management of BRCA-mutation carriers: A single institution experience.

INTRODUCTION: The optimal surgical management of BRCA-mutation carriers remains a subject of debate. To evaluate the appropriateness of breast cancer (BC) treatment, the oncological outcomes of BRCA-mutation carriers treated either with breast-conserving therapy (BCT) or mastectomy were compared. Additionally, the role of bilateral salpingo-oophorectomy (BSO) and potential independent predictive factors for BC treatment were analyzed. MATERIALS AND METHODS: We retrospectively reviewed all the consecutive patients with a pathogenic germline mutation in the BRCA1/2 genes tested at our Institution between July 2008 and October 2018. Primary end-points were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: The characteristics and outcomes of 124 BRCA-associated BC patients were analyzed. Overall, 69 (55.7%) and 55 (44.3%) patients underwent BCT and mastectomy, respectively; 72 (58.1%) patients underwent BSO. After a median interval of 13.3 months, 24 patients underwent mastectomy after primary BCT. There was no significant difference in terms of DFS, DDFS, and OS between patients treated with BCT or mastectomy (p = 0.39,p = 0.27,p = 0.265, respectively). Patients treated with BSO had significantly better DDFS and OS compared to ovarian conservation (p = 0.033,p = 0.040, respectively). Three independent predictive factors for BCT were identified: age ≤41 years, genetic testing performed post-operatively, and breast tumors ≤21 mm. CONCLUSIONS: Our data suggest that BRCA-mutation carriers treated with BCT present similar oncological outcomes compared to mastectomy. Ovarian preservation decreases survival. Young BRCA-mutated patients with small BCs may not need up-front mastectomy, and BSO might be performed when ovarian cancer risk epidemiologically rises and potential reproductive desire is fulfilled.