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Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

The plasmacytoid dendritic cell (pDC) constitutes a unique DC subset that links the innate and adaptive arm of the immune system. Whereas the unique capability of pDCs to produce large amounts of type I IFNs in response to pathogen recognition is generally accepted, their antigen-presenting function is often neglected since most studies on antigen presentation are aimed at other DC subsets. Recently, pDCs were demonstrated capable to present antigen leading to protective tumor immunity. In this review, we discuss how pDCs could be exploited in the fight against cancer by analyzing their capacity to capture, process and (cross-) present antigen.

A reader has called our attention to a printout error in Table S3. Values in column ''cell_id'' in sheet ''seq_stats_total'' were shuffled in the submitted table and are now in the correct order. Tumor origin of two patients (patient 3 and 4) was also mis-labeled, and was corrected from LN (lymph node) to (S)C (subcutaneous). The breakdown of number of cells in each metacell by tumor location in the sheets ''lfp_values_total,'' ''lfp_values_T_NK'' and ''lfp_values_non_T_NK'' has been corrected accordingly. The error has been corrected online. We apologize for any confusion this might have caused.

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T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.

2575 Background: surgery w/wo adjuvant radiotherapy (RT) for (recurrent) advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% 5-year OS, indicating the need for novel treatment options. In recurrent metastatic HNSCC nivolumab nearly tripled the 2-year OS. Aiming at improving clinical outcome in advanced HNSCC in a curative setting, we tested the feasibility of nivolumab ± ipilimumab neoadjuvant to (salvage) surgery w/wo RT. Methods: investigator-initiated phase-IB/II trial to assess feasibility of neoadjuvant nivolumab monotherapy (240 mg in week 1&3: arm-A) or in combination with ipilimumab (1 mg/kg in week 1: arm-B) before surgery (≤ week 5) w/wo RT for advanced HNSCC. Results: 12 patients were included (3+3 design, both arms) in phase-IB of this study; 7/12 (58%) patients had pre-existent moderate-to-severe comorbidities (ACE-27). All patients were HPV negative. All patients received surgery as planned (25-33 days after start of immunotherapy) with no unexpected wound healing problems. In both groups, 4 patients (67%) experienced immune-related toxicity: grade 1-2 (n = 4) and grade 3-4 (n = 1; colitis) in arm-A; grade 1-2 (n = 5) and grade 3-4 (n = 2; colitis and elevated liver enzymes) in arm B. Immune-related toxicity was managed with prednisone (n = 2) and infliximab (n = 1). There was 1/6 (12.5%) pathological response in arm-A (1 near complete response, nCR) and 3/6 (50%) in arm-B (1x partial response and 2x nCR). No patients with nCR had a recurrence at follow-up (median 10 months). Preliminary data (mutational load will be added) show increased H7-B3 gene expression in non-responders before treatment, and increased endothelial cell and NK cell gene expression in responders post-treatment. Overall, in these 12 patients, neoadjuvant ipilimumab + nivolumab resulted in a significant increase in immune-related gene expression when compared to nivolumab only, irrespective of treatment response. Conclusions: neoadjuvant ipilimumab + nivolumab can safely be administered prior to major surgery for advanced HNSCC. Efficacy is promising and will be further evaluated in the phase-II trial continuation. Clinical trial information: NCT03003637.