Killer immune cells destroy cancer cells and cells infected by a virus.
These CD8+ T cells are activated after the detection of viral infection or the growth of “non-self” tumour cells.
However, in chronic viral infection and cancer, the killer cells often lapse into “exhausted” CD8+ T cells that can no longer stem the disease.
This exhaustion is a significant barrier to the effectiveness of new immunotherapies for cancer, including immune checkpoint inhibitors and CAR T cell therapy.
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In a detailed study of exhausted T cell subsets reported in Nature Communications, University of Alabama at Birmingham, USA, 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,” said Shi, a professor in the UAB Department of Radiation Oncology.
“We reason that fine-tuning Gfi1 activity in T cells may prevent or reverse T cell exhaustion to bolster immune checkpoint blockade efficacy.”
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. In contrast, 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 tumour 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 tumour growth in wild-type but not Gfi1 knockout mice.
Similarly, anti-CTLA-4 therapy promoted infiltration and/or expansion of CD4+ and CD8+ tumour-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 tumours,” 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 She, 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 Haematology 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 Centre and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.
