Tumoral Expression of NAC1 Restrains Antitumor Immunity through the LDHA-mediated Immune Evasion

Abstract

Abstract T cell-mediated antitumor immunity has an important role in cancer prevention and treatment; however, immunosuppressive tumor microenvironment (TME) constitutes a major contributor to immune evasion that weakens antitumor immunity. We report here that tumoral expression of nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, negatively impacts the CD8+ T cell - mediated antitumor immunity via through LDHA-mediated suppressive tumor microenvironment. We show that NAC1 could positively regulate the expression of lactate dehydrogenase A (LDHA) at transcriptional level, and LDHA-mediated lactic acid accumulation only inhibited cytokine production but also induced the exhaustion and apoptosis of CD8+ cytotoxic T lymphocytes (CTLs), impairing their cell-killing ability. We further show that in the immunocompetent and immunodeficient mice bearing melanoma, tumors with NAC1 depletion grew significantly slower and had elevated infiltration of tumor antigen specific CTLs following adoptive cell transfer, as compared with the control groups. These findings imply that tumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy such as adoptive cell transfer of CTLs.