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Background: About 30% of patients (pts) with hormone receptor (HR)-positive early breast cancer (EBC) on adjuvant aromatase inhibitor (AI) therapy discontinue due to toxicity with 22% of pts discontinuing during the first year (Henry et al. JCO 2012). For these patients who struggle with adjuvant AIs, there are limited alternatives including switch to a different AI which may have similar side effects, tamoxifen, or observation. This paucity of effective and tolerable options may contribute to poor adherence and/or early discontinuation of adjuvant endocrine therapy, which is associated with worse outcomes. Amcenestrant (SAR439859) is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 first-in-human trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer. The phase 2 window-of-opportunity study AMEERA-4 evaluating two doses of amcenestrant demonstrated robust Ki67 reductions, strong engagement of the ER target, and continued to show a favorable safety profile in an early breast cancer population. Based on pharmacodynamic activity, safety, and emerging results from other ongoing amcenestrant trials, the 200 mg daily dose of amcenestrant was selected for the AMEERA-6 study. Trial Design: This is a prospective, randomized, international, double-blind, double-dummy, phase 3 superiority study of amcenestrant versus tamoxifen. Eligible pts are men and women with any menopausal status with HR+ stage IIB/III breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status. If neoadjuvant systemic therapy was administered, pts must have residual nodal disease after definitive breast surgery (ypN1-3). Pts will be centrally assessed to have ER-positive and/or progesterone receptor-positive (≥10% positive stained cells) status by immunohistochemistry assay. Pts must have received at least 6 months of adjuvant AIs (≥3 months in the adjuvant setting if they received prior neoadjuvant AI) and discontinued within 30 months of initiation due to AI-related toxicity. Pts may have been treated with more than one AI. All adjuvant therapies including chemotherapy, anti-HER2 treatment, cyclin-dependent kinase (CDK) 4/6 inhibitor, and/or poly (ADP-ribose) polymerase (PARP) inhibitors must be completed or stopped prior to randomization. 3738 pts will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily for 5 years and will be followed for 10 years from randomization. Men and pre/peri-menopausal women will also receive a GnRH analog. Extended adjuvant endocrine therapy upon completion of study treatment is allowed per investigator discretion. Stratification factors include duration of prior AI therapy, HER2 status and prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. The primary endpoint is invasive breast cancer-free survival (IBCFS) based on STEEP criteria version 2.0 defined as occurrence of first recurrence of the disease: ipsilateral or regional invasive, distant recurrence, contralateral invasive breast cancer and death. Key secondary endpoint is invasive disease-free survival (IDFS) and other secondary endpoints include overall survival, safety, patient reported outcomes, and pharmacokinetics of amcenestrant. Adherence to treatment and biomarkers are exploratory endpoints. AMEERA-6 recruited the first patient in March 2022 and is being conducted in partnership with AFT, BIG, EORTC, and Sanofi. Clinical trial information: NCT05128773 Citation Format: Otto Metzger, Christina Herold, Coralie Poncet, Heidi De Swert, Jose Casas-Martin, Ann Partridge, Samia Guita, Lisa Carey, Eva Schumacher, Theodora Goulioti, Thomas Meyskens, Joseph Gannon, Khadija Benlhassan, Giovanna Rossi, Eleni Xenophontos, Amal Arahmani, Amylou C. Dueck, Gautier Paux, Etienne Brain, David A. Cameron. AMEERA-6: Phase 3 Study of Adjuvant Amcenestrant Versus Tamoxifen for Patients With Hormone Receptor-Positive Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-04-01.

Purpose Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

The primary objective of this study is to evaluate the clinical significance of RANK/L expression, in both a retrospective cohort of surgically resected stage I-III NSCLC (Lungscape) and a randomized clinical trial-cohort (SPLENDOUR) of advanced NSCLC treated with chemotherapy alone or in combination with denosumab.RANK-L expression was assessed on tissue microarrays (TMAs) in Lungscape and whole sections in SPLENDOUR, using immunohistochemistry, with H-scores values 0 indicating positivity. Prevalence of RANK positivity and its association with clinicopathological characteristics, and patient outcome was explored in a subset of the ETOP Lungscape cohort and in SPLENDOUR. Also investigated were the prevalence of RANK overexpression (proportion of positive cancer cells ≥ 50%) in the Lungscape cohort, and RANK-L in the SPLENDOUR trial.In the Lungscape cohort, RANK expression was assessed at a median follow-up of 46 months (N = 488 patients; 4 centers); 35% were female, 44/49/6% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 48/27/25% with stage I/II/III. Median RFS/TTR/OS were 58/Not reached/74 months. Prevalence of RANK expression was 31% (95%CI:27%-35%); significantly higher in AC: 50% (95%CI:43%-57%) vs SCC: 12% (95%CI:8%-16%) (p 0.001); more frequent in females (42% vs 25%, p 0.001) and tumors ≤ 4 cm (35.3% vs 23.3%, p = 0.0065). No association with outcome was found. In the SPLENDOUR trial (463 patients), the prevalence of membranous and cytoplasmic RANK positivity was 34% (95%CI:30%-38%) and 9% (95%CI:7%-12%), respectively, while prevalence for RANK-L was 5% (95%CI:3%-7%) and 36% (95%CI:31%-40%), respectively. Cytoplasmic RANK-L positivity was more common among females (47% vs 31%, p = 0.001) and in non-SCC histology (45% vs 10%, p 0.0001). At the pre-specified 1% significance level, no prognostic or predictive effect was found.Both cohorts indicate that RANK expression is more common in adenocarcinoma/non-squamous NSCLC and in female patients. No prognostic effect is found, and in the clinical trial involving addition of denosumab to chemotherapy no predictive effect is detected.

Background: Epidemiological studies demonstrate that the incidence of CRC in young adults is continually rising in both Europe and the USA. The differences between the spatial distribution of immune related markers (IRM) and their prognostic role in EOmCRC compared to late onset (LOmCRC) remains to be elucidated. Methods: Forty paraffin embedded formalin fixed unstained sections from patients (pts) diagnosed with either EOmCRC (≤45) or (≥50) LOmCRC, matched for chemotherapy (chx) and molecular features, all with microsatellite stable disease were included. All tissue samples were obtained from pts enrolled in SPECTAcolor (EORTC-40CRC-GITCG) platform trial. The expression of IRM was studied using the GeoMX Digital Spatial Profiler (DSP). Fifty-seven IRMs were used and three morphology markers (MMs) anti-CD45, pan-cytokeratin and SYTO 13. Three 300 μm regions of interest (ROIs) were selected within the core of the tumour and further 3 ROIs within the active margin of the tumour. Each ROI was segmented based on MMs to obtain a tumour microenvironment (TME) and a tumour (T) mask. The analysis used the GeoMX DSP Advanced Analysis Suite software, R and IBM SPSS. Control for multiple comparisons use a false discovery rate (FDR) threshold of 0.05. Results: Samples from 40 pts were collected; 19 (47.5%) were EOmCRCs; 16 (40%) were female; 23 (57.5%) with pathological stage IV. The majority being, 23 (57.5%) grade ≥ 2, left sided 26 (65%), oxaliplatin based first line chx 23 (57.5%). Ten (25%) were KRAS mutant (mt), 1 (2.5%) NRAS mt and 1 (2.5%) BRAF mt. The median overall (OS) and progression free survival (PFS) for the entire cohort was 36.6 months (m) 95%CI (33.5 - 39.7) and 11.7 m (8.1 - 15.3), respectively.The Conclusion: Differential expression analysis of IRMs found IDO1 as differentially expressed in both segments (T and TME). Furthermore, high IDO1 expression seemed to have a dual prognostic role depending on the segment analysed, showing worse OS when found in the tumour but better OS when found in tumour microenvironment for early onset mCRC. Citation Format: Raghavendar Thyagaraja Nagaraju, Jakub Franczak, Markus Möhler, Elisa Fontana, Anne Giraut, Lieve Dirix, Jose Casas-Martin, Beatrice Borelli, Florian Lordick, Elizabeth Smith, Sabine Tejpar, Gunnar Folprecht, Jorge Barriuso. Spatial characterization of immune microenvironment from early onset metastatic colorectal cancer (EOmCRC) showed a dual prognostic role for IDO1 expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6770.

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology.

TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.

Background The analysis of tumour-infiltrating immune cells within patients’ tumour samples in colorectal cancer (CRC) has become an independent predictor of patient survival. The tumour microenvironment and the immune checkpoints, such as PD-L1/PD-1, are relevant to the prognoses and also appear to be relevant for further CRC therapies. Methods We analysed the presence and features of the infiltrated monocyte/macrophage and lymphocyte populations in both tumour and peritumour samples from patients with CRC (n = 15). Results We detected a large number of CD14+ monocytes/macrophages with an alternative phenotype (CD64+CD163+) and CD4+ lymphocytes that infiltrated the tumour, but not the peritumour area. The monocytes/macrophages expressed PD-L1, whereas the lymphocytes were PD-1+; however, we did not find high PD-L1 levels in the tumour cells. Coculture of circulating naïve human monocytes/macrophages and lymphocytes with tumour cells from patients with proficient mismatch repair CRC induced both an alternative phenotype with higher expression of PD-L1 in CD14+ cells and the T-cell exhaustion phenomenon. The addition of an α-PD-1 antibody restored lymphocyte proliferation. Conclusion These results emphasise the interesting nature of immune checkpoint shifting therapies, which have potential clinical applications in the context of colorectal cancer.

Sepsis, among other pathologies, is an endotoxin tolerance (ET)-related disease. On admission, we classified 48 patients with sepsis into 3 subgroups according to the ex vivo response to lipopolysaccharide. This response correlates with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the ET degree. Moreover, the ET-related classification determines the outcome of these patients. Programmed cell death-ligand 1 (PD-L1) expression on septic monocytes is also linked with ET status. In addition to the regulation of cytokine production, one of the hallmarks of ET that significantly affects patients with sepsis is T-cell proliferation impairment or a poor switch to the adaptive response. PD-L1/programmed cell death-1 (PD-1) blocking and knockdown assays on tolerant monocytes from both patients with sepsis and the in vitro model reverted the impaired adaptive response. Mechanistically, the transcription factor hypoxia-inducible factor-1α (HIF1α) has been translocated into the nucleus and drives PD-L1 expression during ET in human monocytes. This fact, together with patient classification according to the ex vivo lipopolysaccharide response, opens an interesting field of study and potential personalized clinical applications, not only for sepsis but also for all ET-associated pathologies.

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry andin vitroassays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-β (TGF-β), in contrast to those from the HV and CPAP groups. High levels of TGF-β were detected in OSA sera. TGF-β release by GARP+monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-β. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.