Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer

Abstract

Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.

Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion

“…Patients with HNSCC are very susceptible to recurrent or new tumors, which are the main cause of death ( Plavc et al, 2020 ). Tumor recurrence was attributed to lateral invasion of small tumor nests beneath the surface epithelium, but the mechanism of lateral invasion is unclear.…”

“…Recurrent/new tumors and metastasis are the main causes of death in patients with HNSCC; these secondary tumors often metastasize and respond poorly to treatment ( Takes et al, 2012 ; Ruzevick et al, 2013 ; Plavc et al, 2020 ). Thus, discovery of biological factors that regulate invasion in HNSCC is essential for identifying new treatment strategies and improving survival, with possible implications for other epithelial-derived tumors.…”

Effective Combinations of Immunotherapy and Radiotherapy for Cancer Treatment

“…Although some clinical studies have confirmed the phenomenon of local RT combined with immunotherapy to stimulate abscopal response, the optimal combination strategy of RT combined with immunotherapy still needs to be further explored (145)(146)(147), including: (1) What are the best sequences to follow when combing RT with immunotherapy? Different studies have shown that the optimal timing of immunotherapy combined with RT is different, which is still controversial at present.…”

Micro-RNAs, the Cornerstones of the Future of Radiobiology in Head and Neck Cancers?

“…The implications of other factors including the microbiome in the synergistic effect of radiotherapy and immunotherapy are still little known. In the context of this new possible indication of radiotherapy, the identification of biomarkers both for the response to treatment with ICI or for radiotherapy–immunotherapy combination is one of maximum interest [ 94 , 95 ].…”