Gfi1 regulates exhausted CD8+ T cells to improve cancer immunotherapy

Killer immune cells destroy cancer cells and cells infected by virus. These CD8⁺ T cells are activated after detection of viral infection or growth of "non-self" tumor cells. However, in chronic viral infection and cancer, the killer cells often lapse into "exhausted" CD8⁺ T cells that no longer can stem disease.

This exhaustion is a major barrier in the new immunotherapies for cancer, including immune checkpoint blockers and CAR T cell therapy. In a detailed study of exhausted T cell subsets reported in Nature Communications, University of Alabama at Birmingham researchers led by Lewis Z. Shi, M.D., Ph.D., show that a transcriptional repressor called Gfi1, or growth factor independent-1, is a key regulator of the subset formation of exhausted CD8⁺ T cells and may offer a key to reducing exhaustion.

Our study identifies an important role of Gfi1 in orchestrating CD8⁺ T cell response to anti-CTLA-4 therapy, the very first U.S. Food and Drug Administration-approved immune checkpoint blocker to treat patients with advanced cancer. We reason that fine-tuning Gfi1 activity in T cells may prevent or reverse T cell exhaustion to bolster immune checkpoint blockade efficacy."

Lewis Z. Shi, M.D., Ph.D., Professor in the UAB Department of Radiation Oncology

Exhausted CD8⁺ T cells are a complex population of subsets composed of progenitor cells and "effector-like" or "terminally exhausted" cells. Effector-like cells still retain some killer ability. The UAB researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108⁺CX₃CR1⁺ subset that expresses low levels of Gfi1, while other established subsets have high expression.

Notable key features of the Ly108⁺CX₃CR1⁺ subset include: First, the Ly108⁺CX₃CR1⁺ subset has a distinct chromatin profile from the other sets, meaning a changed accessibility to certain genes on the chromosome. Second, that subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. Third, this process depends on Gfi1.

To demonstrate a role for Gfi1 in immune checkpoint blockade therapy, the UAB team tested anti-CTLA-4 therapy in a mouse bladder cancer model, comparing mice that had T cells with either wild-type Gfi1 or Gfi1 knockout. They found that the anti-CTLA-4 therapy significantly inhibited tumor growth in wild-type but not Gfi1 knockout mice. Similarly, anti-CTLA-4 therapy promoted infiltration and/or expansion of CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes in wild-type but not Gfi1 knockout mice. These observations were largely corroborated in a second mouse model of colorectal adenosarcoma, MC38.

"Considering Gfi1 downregulation is associated with the active differentiation of CD8⁺ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108⁺CX₃CR1⁺ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors," Shi said.

Along with a recent report by others of promising outcomes in small cell lung cancer from combining a lysine-specific histone demethylase inhibitor with the anti-PD-1 immune checkpoint blocker, "further testing of this combination approach should be conducted in melanoma, bladder cancer and colorectal adenocarcinoma, especially those resistant to immune checkpoint blockers," Shi said.

Co-authors with Shi in the study, "Gfi1 controls the formation of effector-like CD8⁺ T cells during chronic infection and cancer," are Oluwagbemiga A. Ojo, Hongxing Shen and James A. Bonner, UAB Department of Radiation Oncology; Jennifer T. Ingram and Allan J. Zajac, UAB Department of Microbiology; Robert S. Welner, UAB Department of Medicine Division of Hematology and Oncology; and Georges Lacaud, The University of Manchester, Manchester, United Kingdom.

At UAB, Radiation Oncology, Microbiology and Medicine are departments in the Marnix E. Heersink School of Medicine. Shi is a scientist in the O'Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.