Tumor Microenvironment and Immune Response in Lip Cancer

SIMPLE SUMMARY: The presence of tumor-infiltrating lymphocytes (TILs) in the tumor milieu has been linked to better patient prognosis and response to chemo-radiotherapy in head and neck carcinoma, among other malignancies. We studied 60 cases of squamous cell carcinoma of the lip to assess the presence of TILs and their subpopulations and tertiary lymphoid structures (TLSs) in the invading front and inner stroma of the tumor. Thereafter, we investigated the impact of histopathological parameters and prevailing conditions of the tumor microenvironment (TME) in TIL and TLS density. Lip SCCs appeared as more immunogenic compared to other HNCs. Poor lymphocytic infiltration was related to larger tumors, higher invasive ability, dense presence of activated stroma fibroblasts and expression of hypoxia markers. High angiogenic activity was linked with high CD4(+), FOXP3(+), and low CD8(+) TIL density, as well as high CD68(+) macrophage presence. LDH5 expression was linked with high CD4(+) and FOXP3(+) TIL density. ABSTRACT: Tumor-infiltrating lymphocytes (TILs) play a significant role in cancer progression and prognosis of patients. The tumor microenvironment (TME) may affect the anti-tumor immune response. We examined the TIL and tertiary lymphoid structure (TLS) density in the invading front and inner tumor stroma, and the lymphocyte subpopulation (CD8, CD4, FOXP3) density in 60 squamous cell carcinomas of the lip. Analysis was performed in parallel with markers of hypoxia (hypoxia-inducible factor (HIF1α), lactate dehydrogenase (LDHA)) and angiogenesis. Low TIL density in the invading tumor front was related with larger tumor size (p = 0.05), deep invasion (p = 0.01), high smooth-muscle actin (SMA) expression (p = 0.01), and high HIF1α and LDH5 expression (p = 0.04). FOXP3(+) TILs infiltration and FOXP3(+)/CD8(+) ratios were higher in inner tumor areas, linked with LDH5 expression, and higher MIB1 proliferation index (p = 0.03) and SMA expression (p = 0.001). Dense CD4(+) lymphocytic infiltration in the invading front is related to high tumor-budding (TB) (p = 0.04) and angiogenesis (p = 0.04 and p = 0.006, respectively). Low CD8(+) TIL density, high CD20(+) B-cell density, high FOXP3(+)/CD8(+) ratio and high CD68(+) macrophage presence characterized tumors with local invasion (p = 0.02, 0.01, 0.02 and 0.006, respectively). High angiogenic activity was linked with high CD4(+), FOXP3(+), and low CD8(+) TIL density (p = 0.05, 0.01 and 0.01, respectively), as well as high CD68(+) macrophage presence (p = 0.003). LDH5 expression was linked with high CD4(+) and FOXP3(+) TIL density (p = 0.05 and 0.01, respectively). Further research is needed to explore the prognostic and therapeutic value of TME/TIL interactions.