A new way to improve immune checkpoint blockade therapy in CLL
T cell suppression in Chronic Lymphocytic Leukemia (CLL) remains a challenge for immune based therapies. Here we find that suppressing CLL-derived interleukin-10 (IL-10), a potent anti-inflammatory cytokine, can improve T cell function and responses to immune checkpoint blockade.
Immune therapies like immune checkpoint blockade (ICB) revolutionized the treatment of cancer. At its core, the concept is straightforward: enhance natural anti-cancer immune responses to create long-lasting tumor control. T-cells are the prime targets of ICB, as they express tumor antigen specific receptors, generate memory cells, and have capacity for tumor cell lysis making them ideal anti-tumor machines. However, therapies utilizing these powers sometimes fall short in clinical practice.
Many factors contribute to T-cell dysfunction in cancer, which vary from patient to patient, and cancer to cancer. T-cells are pre-programmed to downregulate their activity after repeated stimulation by increasing their expression of inhibitory receptors, leading to a cellular state called exhaustion. This is a normal response to prevent unnecessary damage to the host after an infection is controlled. ICB aims to reverse this process and restore T-cell functionality by blocking exhaustion markers such as programmed death 1 (PD1) or its ligands (i.e. PD-L1). But, many cancers employ multiple methods of immune suppression. B cell Chronic Lymphocytic Leukemia (CLL) is one such malignancy where widespread immune dysfunction includes numerous T-cell deficits and poor responses to anti-PD-1 ICB therapy1,2.
CLL cells produce several immune regulatory molecules, but one notable mention is Interleukin-10 (IL-10). This regulatory cytokine is particularly potent on T-cells, decreasing their anti-cancer activity both directly and indirectly. Previously we showed that removing IL-10 signaling from T-cells improves control of disease in an animal model of CLL where Eμ-TCL1 (de novo mouse CLL cells) are adoptively transferred into immune compromised mice with primed T cells3. Given that IL-10 and PD-L1 downregulate T-cell function by non-redundant mechanisms, we tested combining ICB and IL-10 suppression to restore anti-tumor immunity in this system.
There is more than one way to skin a cat, and there is more than one way to suppress IL-10. We utilized a novel small molecule, MTMox32E, that is an analogue to an old Sp1 inhibitor, mithramycin (plicamycin)4. Sp1 is required for CLL IL-10 production, and this analogue suppressed CLL cell IL-10 secretion. MTMox32E also has a window of therapeutic efficacy where CLL IL-10 is suppressed but anti-tumor T-cell cytokines (IL-2 and interferon-γ) are not. By itself, IL-10 suppression moderately reduced CLL burden, delayed disease progression, and enhanced T-cell effector function in mice.
In our hands anti-PD-L1 therapy in recipient mice (given Eμ-TCL1 CLL and primed CD8+ T-cells) only modestly affected disease and did not improve T-cell functionality. But the addition of IL-10 suppression improved control of CLL in multiple compartments. Compared to ICB alone, a larger proportion of the T-cells from doubly treated mice were in a more functional state (KLRG1+ effector cells and CD27+ memory cells), and there were higher numbers of interferon-γ and Granzyme B expressing CD8+ T-cells. This significantly delayed the progression of disease and increased survival time, even when treatment was ceased 3 weeks prior.
The strategy of combining multiple T-cell immune therapies to improve anti-tumor activity is one that may be applicable to a variety of cancers. Specifically targeting IL-10 could also be used to change the tumor microenvironment and enhance anti-tumor T-cell activity, especially in malignancies with significant immune suppression.
Figure created with BioRender.com
1. Ding, W. et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 129, 3419-3427, doi:10.1182/blood-2017-02-765685 (2017).
2. Forconi, F. & Moss, P. Perturbation of the normal immune system in patients with CLL. Blood 126, 573-581, doi:10.1182/blood-2015-03-567388 (2015).
3. Alhakeem, S. S. et al. Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity. J Immunol 200, 4180-4189, doi:10.4049/jimmunol.1800241 (2018).
4. Liu, Y. et al. Mithramycin 2'-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy. J Med Chem 63, 14067-14086, doi:10.1021/acs.jmedchem.0c01526 (2020).