CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: A Review

Abstract

CD8⁺ tumor-infiltrating lymphocytes (TILs) are increasingly used in oncology as a prognostic and predictive tool to guide patient management. This review summarizes current literature on CD8⁺ TILs in head and neck squamous cell carcinoma (SCC). Published meta-analyses and clinical trials evaluating CD8⁺ TILs were analyzed. Consistent positive associations between elevated CD8⁺ TILs and overall survival have been observed across head and neck sites. CD8⁺ TILs have been found to predict response to treatment, most commonly immunotherapy, but also chemoradiation. Numerous trials have shown that increased CD8⁺ TIL frequencies in pretreatment biopsies could identify patients likely to respond to neoadjuvant therapies. CD8⁺ TIL infiltration has also been elevated in responders both during and after treatment. However, wider adoption of CD8⁺ TIL quantification as a biomarker has been limited by the need for clinical validation and universal measurement guidelines for head and neck SCC, as there are for other malignancies. Measurement variability includes which tumor compartment is sampled, how TILs are quantified, and which cutoffs are clinically relevant. For several head and neck SCC, measurement of CD8⁺ TILs in the central or intratumoral compartment, followed by the stromal compartment, has been most consistently associated with survival. Future studies are needed to evaluate subpopulations of CD8⁺ TILs and biomarker-based treatment selection.

FIG 1.

Tumor subcompartments of an exemplary head and neck SCC. In panel (A), a whole-slide digital image displays a section of the SCC, revealing the T with invasion into the adjacent M. A black arrow points to the invasive front of the tumor, and N represents the background normal squamous mucosa. In panel (B), the T compartment is outlined by a black solid line, whereas the tumor’s invasive front is delineated by a yellow dashed line. The adjacent muscle is denoted by M. Panel (C) provides a high-power view of the tumor compartment, highlighting the TC with a yellow dashed line and the S. M, muscle; S, stroma; SCC, squamous cell carcinoma; T, tumor; TCs, tumor cells.

FIG 2.

Examples of high CD8⁺ TILs (A-C) and low CD8⁺ TILs (D-F) for head and neck SCC. The figure illustrates examples of SCC with high (A-C) and low (D-F) CD8 expression levels. Panel (A) displays an SCC with prominent TILs, whereas panel (B) shows the CD8⁺ immunostain of the same case, revealing frequent immunoreactive cells. Panel (C) depicts the markup result of quantitative image analysis, with red and orange highlights indicating positive cells and blue highlights indicating negative cells. In contrast, panel (D) showcases an SCC with no obvious TILs. Panel (E) displays the CD8 immunostain of the same case, revealing only rare immunoreactive cells. Panel (F) presents the markup result of quantitative image analysis, with red and orange highlights indicating rare positive cells and blue highlights indicating negative cells. SCC, squamous cell carcinoma; TILs, tumor-infiltrating lymphocytes.