Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: The outcome of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) has not changed for the past decade despite advances in treatment strategies. SLC3A2, which encodes CD98hc, was identified as a putative biomarker for HNSCC radioresistance. Chimeric antigen receptor (CAR) T cell therapy presents a promising immunotherapy approach for the treatment of different cancer types. Due to the limitations of this system, including a lack of self-control mechanisms, the adapter UniCAR system with a switchable mechanism was developed. This study demonstrated a synergistic effect of the combination of fractionated irradiation and immune targeting of CD98hc. The sequential combination of fractionated radiotherapy and UniCAR-based immunotherapy revealed itself to be a promising approach for the treatment of high-risk HNSCC patients. ABSTRACT: Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.