Tumor-Infiltrating T Cell Receptor-Beta Repertoires are Linked to the Risk of Late Chemoradiation-Induced Temporal Lobe Necrosis in Locally Advanced Nasopharyngeal Carcinoma.

Abstract

Temporal lobe necrosis (TLN), a late complication of nasopharyngeal carcinoma (NPC) after concurrent chemoradiotherapy (CCRT), causes permanent neurologic deficits. We aimed to investigate the risk factors for the development of CCRT-induced TLN in locally advanced NPC patients. The incidence of CCRT-induced TLN was assessed in consecutive patients with NPC initially staged with T_3-4N_0-3M₀ receiving curative intensity modulated radiation therapy (IMRT) and cisplatin-based chemotherapy with long-term follow-up. The TLN risk was evaluated with radiation dose-volume histograms (a dosimetric risk indicator of organ injury) and the dynamics of blood circulating neutrophil-to-lymphocyte ratios (a clinical indicator of systemic inflammation) by linear and logistic regression models. High-throughput unbiased T cell receptor-beta (TCR_beta) sequencing was performed to correlate the different TCR_beta repertoires of NPC-infiltrating lymphocytes (a biological factor of the immune microenvironment) with TLN incidence. In the era of modern IMRT-based CCRT, radiation doses of up to 74 Gy achieved local control rates of more than 90% in both T₃ and T₄ diseases but still induced a remarkably higher incidence of TLN in the T₄ patients (30.14%) compared with the rare incidence of TLN observed in the T₃ patients (2.78%) (P < .0001). We found that in the T₄ NPC patients, univariate and multivariate analyses showed the radiation tolerance dose-volume effect was not an absolutely independent factor influencing TLN occurrence. However, increased TLN risk was observed in association with higher pre-CCRT baseline and post-CCRT neutrophil-to-lymphocyte ratios. There was also a link between intratumoral TCR_beta repertoire subtypes and TLN incidence. Combining the inherent TCR_beta genomic susceptibility with the clinical variable neutrophil-to-lymphocyte ratio better predicted the risk of TLN for T₄ NPC patients after CCRT. The associations of tumor-infiltrating lymphocyte repertoires and blood circulating neutrophil-to-lymphocyte ratios with TLN occurrence in T₄ NPC patients suggest that the immune and inflammatory milieus play roles in the late brain damage caused by CCRT. Modulated or provoked by CCRT locally and systemically, the reciprocal interactions of neutrophils and lymphocytes in the intracranial NPC-associated immune microenvironment could be a key driver of chronic TLN pathogenesis.