Abstract
Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.
Highlights
EZH2 (Enhancer of Zeste Homolog 2) inhibitors (EZH2i) are being tested in the clinic in multiple cancer indications, and this targeted cancer therapy is approved for use in epithelioid sarcoma and relapsed/refractory follicular lymphoma [1, 2]
Total proliferating cells marked by Ki-67 expression were relatively equal (Figure 1B); the increase in activated KLRG1+ CD8+ T cells mediated by a4-1BB was reduced at 100 mg/kg EZH2 inhibitors (EZH2i), in the blood (Figure 1C)
We show that using EZH2i can compromise the efficacy of a4-1BB using in vivo syngeneic tumor models and link this to the loss of cytotoxic CD8+ T cell populations
Summary
EZH2 (Enhancer of Zeste Homolog 2) inhibitors (EZH2i) are being tested in the clinic in multiple cancer indications, and this targeted cancer therapy is approved for use in epithelioid sarcoma and relapsed/refractory follicular lymphoma [1, 2]. EZH2i are reported to affect immune cells, notably by decreasing Treg suppressive capacity [9]. These mechanisms all enhance the recruitment and activation of the immune system, CD8+ T cells [9, 11, 12]. These studies would suggest that EZH2 may be dispensable for T cell function, models of graft versus host [13, 14], acute viral infection [15, 16], and melanoma [17], would suggest a T cell-intrinsic requirement for effector cells
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