41BB (CD137) is a costimulatory receptor transiently upregulated on T cells following activation. 41BB is activated by its ligand 41BBL (TNFSF9), a TNF receptor superfamily member expressed by activated antigen presenting cells and anti-41BB agonistic antibodies are in clinical trials for cancer immunotherapy. In a recent article in The Journal of Experimental Medicine, Curran et. al demonstrate that 41BB activation of T cells leads to the generation of a novel subset of CD4+ and CD8+ T cells dependant on the master transcription factor Eomesodermin (Eomes).
Activation of 41BB on T cells leads to enhanced T cell survival. Anti-41BB-agonistic antibodies have demonstrated significant anti-tumor activity in mice by enhancing anti-tumor cytotoxic T cell responses. Thus, there are currently several clinical trials underway exploring the efficacy of anti-41BB-agonist antibodies in several types of cancers, including melanoma, renal carcinoma, ovarian cancer, and lymphoma. In a previous study by the same group (Curran et. al, PLoS One, 2011), an observation was made that a unique subset of T cells infiltrated B16 melanoma tumors in mice after anti-41BB-agonistic antibody treatment. These T cells expressed the inhibitory receptor KLRG1, and elicited strong anti-tumor activity. Thus, in the current study, the authors sought to further characterize this T cell subset in mice.
To define the phenotype and functions of tumor-associated KLRG1+ versus KLRG1– T cells types, T cells were isolated from B16 tumors established in mice, following treatment with anti-41BB antibodies plus irradiated Flt3-ligand–expressing B16 cells (FVAX) or FVAX alone. The addition of FVAX further enhanced the tumor-infiltrating frequency of KLRG1+ T cells elicited by anti-41BB antibodies. Gene expression analysis revealed that KLRG1+ CD4+ and CD8+ T cells expressed significantly higher levels of cytoxicity genes: multiple granzymes, perforin, and FasL, than KLRG1– T cells. In vitro cytotoxicity assays with B16 melanoma cell targets demonstrated enhanced killing capacity of KLRG1+ compared with KLRG1– CD4+ and CD8+ T cells.
Superior cytotoxic functions are generally associated with CD4+ TH1 and CD8+ TC1 T cell subsets, dependant on the transcription factor T-bet (TBX21). However, analysis of expression of the known master transcription factors governing different T cell subsets, found that expression of Eomes but not T-bet was elevated in KLRG1+ T cells. Runx3 expression was also slightly elevated in KLRG1+ versus KLRG1– T cells. Furthermore, transgenic mice lacking Eomes expression in CD4+ cells (CD4-CRE/Eomesflox/flox) did not develop tumor-infiltrating KLRG1+ T cells after anti-41BB antibody treatment, demonstrating the necessity of Eomes for development of these cells, even when Eomes expression is only absent in the CD4+ T cell compartment. Thus, these novel subsets of KLRG1+ T cells were termed CD4+ THEO and CD8+ TCEO T cells.
Interestingly, KLRG1+ T cells play a role not only in anti-tumor immunity, but were induced and found at significant levels in spleens and livers from mice infected with Listeria Monocytogenes or LCMV.
As this is a newly described T cell subset, many questions remain. However, most relevant is whether equivalents of these cells exist in humans, and the roles they play in human diseases.
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