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. 2020 May 7;3(6):e201900545. doi: 10.26508/lsa.201900545

Figure 5. CD8+ T-cell–inflamed and cytolytic features of MAPK-mutated head and neck squamous cell carcinoma (HNSCC) were recapitulated in immunocompetent models with massive apoptosis in situ.

Figure 5.

(A) Nonhierarchical clustering of tumor infiltrating immune cell types and immune signature scores (CYT, T-effector signature and IFN-γ functionality score) in TCGA HNSCC tumors with MAPK pathway mutational status and HPV status. (B) High infiltrating levels of CD8+ T-cells are associated with markedly improved HNSCC patient survival compared with patients with low CD8+ T-cell infiltration levels (top and bottom 20% cutoffs). (C) Immunohistochemical staining of MAPK pathway-mutated HNSCC tumors (T40 with MAPK1 p.D321N hotspot mutation) showing increased expressions of the CD8 marker (for CD8+ T infiltration). These tumors also expressed higher levels of CD11c marker (for dendritic cell infiltration) and neutrophil elastase marker (for neutrophil infiltration) when compared with MAPK-WT tumors (T69). Scale bars are shown. (D) Increased expressions of CD8 marker (for CD8+ T infiltration) were detected in mHRAS p.G12V mutant, mMAPK1 p.D319N mutant (corresponding to MAPK1 p.D321N mutation in human MAPK1), and mMAPK1 p.E320K mutant (corresponding to MAPK1 p.E322K mutation in human MAPK1), and in their respective mouse WT xenografts by immunohistochemistry on day 6 (for mMAPK1 WT versus mMAPK1 p.E320K pair) and on day 11 (for mHRAS WT versus mHRAS p.G12V & mMAPK1 WT versus mMAPK1 p.D319N pairs) after tumor cell inoculation. (E) Dramatic increases of apoptotic cells were also observed in MAPK pathway-mutated tumors labeled with TUNEL and corresponding DAPI staining on day 6 after tumor cell inoculation. (F, G, H) Kaplan–Meier overall survival (OS) curves for HNSCC patients with (F) higher IFN-γ functionality score, (G) higher T effector signature score, and (H) higher CYT score and versus patients with respective lower IFN-γ functionality, T-effector signature and CYT score in TCGA HNSCC (N = 522) RNA-seq cohort (top 20% and bottom 20% cutoffs). (I) Kaplan–Meier OS curves for MAPK pathway mutated patients with high IFN-γ functionality score and high T-effector signature score and high CYT score (all top 20% cutoffs), demonstrating long OS (median OS not reached).