TIM-3 and CEACAM1 are Prognostic Factors in Head and Neck Squamous Cell Carcinoma

Abstract

Background: T-cell Immunoglobulin and Mucin domain-containing molecule-3 (TIM-3) is a new immune checkpoint molecule which plays important and complex roles in regulating immune responses and in inducing immune tolerance. TIM-3 is expressed on activated T cells and its signaling on cytotoxic T cells leads to T cell exhaustion which is mediated by carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on tumor tissues and/or tumor infiltrating lymphocytes (TILs).Methods: In the present study, we investigated TIM-3 and CEACAM1 immunohistochemical expression in 80 head and neck squamous cell carcinoma (HNSCC) specimens, linked to detailed outcome, clinic-pathological parameters. Here we reported scores and absolute counts of TIM-3+/CEACAM1+ TILs, and evaluated the expression of CEACAM1 on tumor tissues.Results: The results showed that more TIM-3+ TILs infiltration correlated with poorer overall survival (p < 0.001), as did the presence of CEACAM1 on cancer cells (p < 0.001) and CEACAM1+ TILs in tumor microenvironment (p = 0.015). Multivariate Cox regression analysis revealed that high TIM-3+ TILs may be considered as an independent prognostic factor of poor disease outcome (hazard ratio, 2.066; 95% confidence interval, 1.027–4.159; p = 0.042), as well as cancer cells expressed CEACAM1 level (hazard ratio, 5.885; 95% confidence interval, 2.832–12.230; p < 0.001).Conclusion: Our results indicate that expression of TIM-3 and CEACAM1 may represent a highly dysfunctional population of T cells. Our current findings suggest both of them were valuable predicting markers that might provide help for clinicians to design effective immunotherapeutic regimen against head and neck carcinoma.

Neutrophil Extracellular Traps in Cancer Therapy Resistance

“…TIM-3 and CEACAM1 co-expression was thus associated with an immunosuppressive TME conducive to cancer progression and therapy resistance ( Figure 1 ) [ 121 ]. These results were later corroborated in clinical cohorts of colorectal and head and neck cancer patients underscoring the clinical relevance of this work [ 123 , 124 ]. With that said, it stands to reason that therapeutically targeting NETs in conjunction with CEACAM1 could potentially restore sensitivity to immunotherapy, but this hypothesis remains to be tested.…”

“…A growing number of pre-clinical and clinical studies have in turn associated CEACAM1 with resistance to systemic therapy [ 119 , 120 , 121 , 122 , 123 , 124 ]. Ortenberg et al [ 122 ] conducted a longitudinal retrospective study to evaluate association between serum CEACAM1 expression and response to immunotherapy in progressive melanoma patients, reporting that the protein was elevated over time in poor responders.…”

Immunotherapy Approaches in HPV-Associated Head and Neck Cancer

“…TIM-3 is an immune checkpoint coreceptor present on activated T-cells and mediates reduced proliferation and production of effector cytokines and apoptosis of effector T-cells [ 48 ]. A recent study examined expression of TIM-3 in 80 HNSCC specimens and its correlation with clinical and pathological outcomes [ 48 ]. Increased TIM-3-positive tumor-infiltrating lymphocytes correlated with worse OS ( p < 0.001).…”

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

“…TIM-3 expression is increased in CD8 + TILs in solid tumors, and correlates with poor outcome in several tumor types, among which include neck squamous cell carcinoma [ 170 ], urothelial carcinoma [ 171 ] and colorectal cancer [ 172 ]. However, much remains to be understood about the circuitry by which TIM-3 operates to mediate its effects in different tumoral contexts.…”