In the newest issue of Cancer Discovery, researchers in the US and Spain report on the HIF-1α hypoxia response in tumor-infiltrating T lymphocytes. They found that CD8 and CD4 tumor-infiltrating T lymphocytes from colon carcinomas, melanomas, and spontaneous breast adenocarcinomas transplanted into mice are CD137-positive and that the expression of CD137 on activated T lymphocytes is enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine. "Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α–knockout T cells, and such HIF-1α–deficient T cells remain CD137-negative even when becoming [tumor-infiltrating T lymphocytes], in clear contrast to co-infiltrating and co-transferred HIF-1α–sufficient T lymphocytes," the team writes. In exploiting CD137's selective expression on TILs, the team was able to confine the effects of subsequent immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue, sparing normal tissue. "As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade," they add.
Also in Cancer Discovery, researchers at the Washington University School of Medicine in St. Louis describe their development of a bioluminescent transposon reporter-trap that could be used to identify tumor-specific microenvironment-induced promoters in Salmonella, as part of a conditional bacterial-based tumor therapy. The team designed a custom promoterless transposon reporter containing bacterial luciferase to characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, and then exposed the reporter to melanoma or colon carcinoma cells. This identified five bacterial genes activated by cancer cells, they write — adiY, yohJ, STM1787, STM1791, and STM1793. "Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specific, and reversible stimulus for activation of these Salmonella genes in vitro and in vivo," the team adds. "Furthermore, Salmonella expressing Shiga toxin from the STM1787 promoter provided potent and selective antitumor activity in vitro and in vivo, showing the potential for a conditional bacterial-based tumor-specific therapeutic."