HIF-1 & alpha; regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors

CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., a non-conventional form of the cd5 gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1 & alpha; onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.

Automated summary

CD5, an inhibitor of T-cell receptor (TCR), is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME) due to preferential transcription of a non-conventional form of the cd5 gene. Hypoxia, a mechanism employed by tumors to evade anti-tumor response, leads to decreased surface CD5 expression and increased cytoplasmic accumulation in T cells through HIF-1α regulation. This hypoxia-driven mechanism was validated in colorectal cancer (CRC) patient samples.