Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide
1-year survival and response rates of anti-PD-1 in HNSCC were only 36 and 14%, respectively, which highlights the urgent need to identify novel therapeutic options to increase the effectiveness of immune checkpoint blockade (ICB) for >80% of patients that do not have an objective response to anti-PD-1/programmed death ligand 1 (PD-L1) treatment[13,14,15]
We developed a panel of C57Bl/6derived syngeneic cells that resemble human HNSCCs closely with unique features: (i) The HNSCC cells have nearly identical tobacco-associated mutational signatures and genomic aberrations; (ii) they can be orthotopically transplanted into the tongue of immunocompetent C57Bl/6 mice; (iii) the tumors are histologically HNSCCs with abundant lymphangiogenesis and potential for lymph node metastasis; and (iv) the tumors exhibit abundant immune infiltration and are immunogenic, the latter as judged by their ability to induce immunological memory when used to vaccinate mice
Summary
TCGA 4MOSCs HPV(–) 1 2 3 4 Kmt2b 2.9% Kmt2c 8.6% Kmt2d 17.7% Wwtr1 0% Cdh10 7.4% Keap1 4.9% Hras 4.5% Nf1 2.5% Ctnnb1 0.8% Pten 1.6%. Growth factors (such as G-CSF, GM-CSF) than in 4MOSC1 tumors, which may contribute to the recruitment and survival of MDSCs and inflammatory cells, as well as VEGF that may explain the higher density of lymphatic vessels (Supplementary Fig. 3) To determine whether this immune infiltration is associated with antigen-driven immunogenicity, we investigated whether the 4MOSC tumors could generate memory immune responses. Our results suggest that these syngeneic HNSCC cell lines are highly immunogenic (Supplementary Fig. 4) These findings indicate that these mice are capable of generating adaptive immune responses against 4MOSC tumor antigens. Upon anti-PD-1 treatment, there were significant increases in LAG-3 and TIM-3, and greater increase in CTLA-4 in CD8 T cells isolated from the αPD-1 resistant tumors when compared with their parental tumors, while increases in LAG-3 in CD4 T cells were comparable between parental and αPD-1 resistant tumors (Supplementary Fig. 8)
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