Additionally, HPV-negative tumors present a greater abundance of fibroblasts and fibroblast-enriched neighborhoods, where all T cells display reduced expression of activation markers such as CD44, HLA-A, CD45RO, ICOS, and Granzyme B. These findings suggest that fibroblasts may also contribute to a physical barrier that limits anti-tumor activity, reinforcing the “cold” immunosuppressive nature of these tumors [43, 44]. Here, ICOS is linked to neoplasm.