# The Role of Tumor Immune Microenvironment and Clinical Factors in Head and Neck Cancer Prognosis Among African American Men and Women

## TL;DR

This study finds that biological differences in tumor immune environments may explain why African American women with head and neck cancer live longer than men.

## Contribution

The study introduces spatial transcriptomic profiling to reveal sex-specific immune differences in tumor microenvironments among African American HNSCC patients.

## Key findings

- Male tumors showed limited immune infiltration and more exhausted T cells compared to female tumors.
- Female tumors displayed higher proportions of T and B cells, indicating a more active immune microenvironment.
- Clinical and socioeconomic factors did not fully explain survival differences between the sexes.

## Abstract

Head and neck cancer affects hundreds of thousands of people worldwide each year, and survival outcomes are worse in African American patients. Prior studies have shown that African American women with this cancer live longer than African American men, but the reasons for this difference are not well understood. In this study, we examined clinical, social, and biological factors to better understand why this survival gap exists. We found that men and women had similar access to care, treatment patterns, and medical conditions, suggesting these factors do not fully explain the difference in outcomes. Using advanced tissue analysis, we observed that tumors from women showed stronger immune activity, while tumors from men had weaker immune responses. These findings suggest that biological differences in the tumor environment may contribute to survival disparities and could help guide more personalized cancer treatments in the future.

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) causes half a million deaths each year; therefore, it is essential to understand the factors that affect patient prognosis. Many studies fail to investigate the biological drivers behind survival disparities, especially sex-specific differences within racial groups. This study serves as a foundational project to begin elucidating biological differences in the tumor microenvironment between male and female African American HNSCC patients. Methods: A total of 111 patients who were diagnosed with HNSCC and identify as African American were grouped by sex. Analyses of socioeconomic status, co-morbidities, tumor characteristics, and treatment were conducted. Spatial transcriptomic analysis was performed on four randomly selected primary HNSCC tumor tissues. Results: No sex-based differences were observed in socioeconomic measures, treatments, tumor stage, follow-up, recurrence, or cause of death (all p > 0.15), though females had higher median income than males (p = 0.035). Comorbidity profiles were also largely comparable between males and females. Evaluating tumor microenvironments, we found that male tumors were dominated by malignant cells and fibroblasts, with limited adaptive immune infiltration. By contrast, female tumors displayed markedly higher proportions of immune cells, including T cells and B cells. Male tumors harbored sparse T cells, largely skewed toward exhausted phenotypes while female tumors displayed abundant T cell infiltration consistent with immunologically active tumor microenvironment. Conclusions: Clinical and demographic factors showed minimal sex-based differences among African American HNSCC patients, spatial transcriptomic profiling revealed strikingly distinct immune microenvironments by sex. These findings suggest that biological, rather than simply clinical, differences may drive survival disparities. This project serves as a novel and foundational study promoting the use of spatial transcriptomics to evaluate possible survival disparities within HNSCC populations to alleviate survival disparities.