No abstract

Microenvironmental conditions control the entrance and thriving of cytotoxic lymphocytes in tumors, allowing or preventing immune-mediated cancer cell death. We investigated the role of tumor-infiltrating lymphocyte (TIL) density in the outcome of radiotherapy in a series of squamous cell head–neck tumors (HNSCC). Moreover, we assessed the link between markers of hypoxia and TIL density. One-hundred twenty-one patients with HNSCC treated prospectively with radical radiotherapy/chemo-radiotherapy were analyzed. The assessment of TIL density was performed on hematoxylin and eosin biopsy sections before radiotherapy. TIL density ranged from 0.8 to 150 lymphocytes per ×40 optical field (median 27.5). Using the median value, patients were grouped into two categories of low and high TIL density. Early T-stage tumors had a significantly higher TIL density (p < 0.003), but we found no association with N-stage. Overexpression of HIF1α, HIF2α, and CA9 was significantly linked with poor infiltration by TILs (p < 0.03). A significant association of high TIL density with better disease-specific overall survival and improved locoregional relapse-free survival was noted (p = 0.008 and 0.02, respectively), which was also confirmed in multivariate analysis. It is concluded that HNSCC phenotypes that allow for the intratumoral accumulation of lymphocytes have a better outcome following radical radiotherapy/chemo-radiotherapy. Intratumoral-activated HIF- and CA9-related pathways characterize immunologically cold tumors and may be used as targets for therapeutic interventions.

Background The presence and activity of tumor-infiltrating lymphocytes (TILs) is a key parameter related to the antitumor immune response. A large number of studies reveal TIL density as a prognostic marker and predictor of response to radiotherapy, chemotherapy, and immunotherapy. Methods We examined the TIL and tertiary lymphoid structure TLS density in the invading front and inner tumor stroma, in a 33 squamous cell laryngeal carcinomas (LSCC) treated with laryngectomy. TIL and TLS densities were in parallel examined with markers of anaerobic metabolism, vascular density (VD), vascular survival ability (VSA), and histopathological parameters. Results TIL and TLS densities significantly decreased in inner tumor areas (p < 0.0001). TIL density in the invading tumor front was inversely related with lymph node involvement (p = 0.03), HIF1α expression (p = 0.008), vessel density (p = 0.02), and MIB1 (p = 0.006). TIL density in inner stroma was inversely linked to local invasion (marginal p = 0.05), tumor budding (TB) (p = 0.005), MIB1 (p = 0.02), and HIF1α expression (p = 0.02). Low-TLS density in the invading front and in inner tumor areas was related to high TB (p = 0.02 and 0.002, respectively), HIF1α (p = 0.003 and 0.01, respectively), and LDH5 expression (p = 0.003 and 0.007, respectively). CD4+, FOXP3+ TIL density, and FOXP3+/CD8+ ratio were directly associated with VSA (p = 0.008, 0.02, and 0.05, respectively). Conclusion Poor immune response is related to hypoxic background and anaerobic metabolism, as well as increased invasive and metastatic ability. Regulatory TIL markers are linked with increased angiogenic potential. The prognostic, predictive, and therapy-guiding value of TILs in clinical practice demands thorough investigation.