The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.

Accurate predictive biomarkers of response to immune checkpoint inhibitors (ICIs) are required for better stratifying patients with cancer to ICI treatments. Here, we present a new concept for a bioassay to predict the response to anti-PD1 therapies, which is based on measuring the binding functionality of PDL1 and PDL2 to their receptor, PD1. In detail, we developed a cell-based reporting system, called the immuno-checkpoint artificial reporter with overexpression of PD1 (IcAR-PD1) and evaluated the functionality of PDL1 and PDL2 binding in tumor cell lines, patient-derived xenografts, and fixed-tissue tumor samples obtained from patients with cancer. In a retrospective clinical study, we found that the functionality of PDL1 and PDL2 predicts response to anti-PD1 and that the functionality of PDL1 binding is a more effective predictor than PDL1 protein expression alone. Our findings suggest that assessing the functionality of ligand binding is superior to staining of protein expression for predicting response to ICIs.

Therapies targeting the PD-1/PD-L1 pathway have transformed head and neck squamous cell carcinoma (HNSCC) treatment. However, predicting the response to anti-PD-1 therapy remains a clinical challenge. This study evaluated the functional binding of PD-1 ligands in 29 HNSCC patients and compared it to the standard PD-L1 Combined Positive Score (CPS). The assessment of PD-1 ligands’ functionality advances the current ability to predict the response of HNSCC patients to anti-PD-1 therapy.

HLA-E presenting the HLA-G leader peptide VMAPRTLFL (HLA-E[pHLA-G]) on tumor cells plays a crucial role in suppressing natural killer (NK) and cytotoxic CD8+ T cells through NKG2A interaction. While blocking HLA-E:NKG2A is a promising immune checkpoint (IC) approach in cancer therapy, toxicity remains a major clinical concern. We developed a novel IC inhibitor that selectively prevents HLA-E:NKG2A interaction, a monoclonal antibody that selectively targets the HLA-E[pHLA-G] complex, distinguishing cancerous from noncancerous cells. In clinical bone marrow samples from patients with multiple myeloma (MM), 4D7 specifically recognized tumor-associated HLA-E–peptide complexes. Using NK cells from healthy donors, 4D7 effectively blocked the HLA-E:NKG2A interaction, and enhanced NKG2A-positive NK cell activity in autologous MM cell cocultures. Importantly, 4D7 did not inhibit NKG2C-positive NK cells, preserving their activity, even though NKG2C also interacts with HLA-E. In MM-bearing mice treated with human NK cells, 4D7 significantly reduced tumor growth. This targeted approach activates NK cells only against tumor cells presenting HLA-E–peptide complexes, potentially minimizing toxicity compared with current NKG2A inhibitors. The development of 4D7 highlights a promising advancement in immunotherapy for hematologic malignancies, offering improved outcomes for patients with MM, and a foundation for broader application across cancer types.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a transformative approach for cancer treatment, demonstrating remarkable success in patients with relapsed and refractory hematological malignancies. However, challenges persist in optimizing CAR-T cell production and improving therapeutic outcomes. One of the major hurdles is the efficiency of retroviral or lentiviral transduction during CAR-T cell manufacturing. Additionally, the heterogeneity of T-cell populations isolated from patients can impact CAR-T cell effectiveness and persistence in vivo. This article explores a novel strategy to address these challenges by focusing on serum-free medium and additive optimization. We propose a unique approach that incorporates the culturing of T cells in Nutri-T medium, along with 24 h of exposure to combined low concentrations of BX795 and rosuvastatin, to enhance the transduction efficacy and functionality of CAR-T cells. The results presented here provide promising insights into the potential of this strategy to produce more effective CAR-T cells for immunotherapy, ultimately advancing the field and benefiting cancer patients worldwide.