Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

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.

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer

“…An important finding was also the association of HIF1α with low infiltration of PCs with TILs in accordance with previous studies in breast and head–neck cancer [ 27 , 28 ]. A hypoxic and acidic TME provides a functional barrier against cytotoxic lymphocytes, blocking their proliferation and cytotoxic activity, and furthermore, promotes regulatory T-cell and monocyte prevalence [ 6 – 10 ].…”

Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer

“…Many studies support the importance of quantitative and qualitative characteristics of the immune infiltrate in the prognosis of patients. In particular, tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are found to have an impact in patient’s prognosis in a variety of solid tumors, including head–neck carcinomas [ 11 , 12 , 16 , 19 – 21 ].…”

“…Tumor-infiltrating lymphocytes (TILs) are known to affect the prognosis of HN cancer patients [ 11 ], as well as the response to RT and chemotherapy [ 12 ]. As a tumor grows in a microenvironment with abnormal dysfunctional vasculature and poor oxygen availability, cancer cells use anaerobic glycolysis to cover their metabolism needs.…”

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

“…For instance, a study on head and neck cancer observed that the frequency of infiltrated TILs into the tumor site increased following radiotherapy and chemo/radiotherapy. Furthermore, this investigation reported that the expression of HIF-α as a hypoxia indicator decreased following the combination therapy ( 203 ).…”