Oral squamous cell carcinoma (OSCC) includes cancers of the oral cavity, lip and oropharynx. One of the risk factors for the development of OSCC is long-term infection with high-risk genotypes of human papillomavirus (HPV). The standard treatment for locally confined OSCC consists of surgical removal of the lesion or irradiation. However, for advanced or metastatic disease, other forms of systemic treatment such as chemotherapy or immunotherapy with immune checkpoint inhibitors (ICI) against the programmed cell death receptor (PD-1) are also used. Unfortunately, less than 20% of patients respond to ICI treatment alone, so combination treatment approaches are being explored to increase the effectiveness of immunotherapy. One of these approaches is the use of radiotherapy which can induce immunogenic cell death of tumor cells. Because lymphocytes are very sensitive to irradiation (IR), partial-volume irradiation (pIR) is also being investigated with the aim of immunomodulation. It is hypothesized that pIR could preserve more lymphocyte-derived immune cells in the non-irradiated part of the tumor, which could increase the efficacy ICI by inducing immunogenic cell death of tumor cells in the irradiated part. The immunological effects of pIR in HPV-positive and HPV-negative OSCC have not yet been investigated. Such studies require immunocompetent mouse tumor models, which are limited in HPV-positive OSCC due to the species specificity of HPV. In this doctoral thesis, we established two tumor models of HPV-positive OSCC and characterized them at in vitro and in vivo levels. One of the tumor models, MOC1-HPV K1, showed increased radiosensitivity to irradiation with a single dose of 15 Gy, which coincides with a lower level of hypoxia in the tumor microenvironment and corresponds to the improved response of patients with HPV-positive oropharyngeal OSCC observed in the clinic. Both the HPV-negative MOC1 tumor model and the HPV-positive MOC1-HPV K1 tumor model have the characteristics of immunosuppressive tumors with a majority of immunosuppressive myeloid cells, mainly neutrophils. IR or pIR did not induce significant differences in the infiltration of immune cells into the tumor microenvironment of MOC1 or MOC1-HPV K1 tumors and therefore did not significantly improve the efficacy of ICI therapy compared to IR or pIR alone. In mice that responded to the combination therapy, a higher proportion of cytotoxic T cells was detected. Therefore, we hypothesize that further optimization of radiation dosing and timing of checkpoint inhibitor administration relative to irradiation could induce more immunologically favorable changes, potentially resulting in a better antitumor response.
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