Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T Cell Rejection Function in Tumors

By Jaikumar Duraiswamy, K. Kaluza, G. Freeman, George Coukos. Cancer Research, 2013

700 citations recorded by the source corpus.

Tumor progression is facilitated by regulatory T cells (Tregs) and restricted by effector T cells. In this study, we document parallel regulation of CD8+ T cells and Foxp3+ Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8+ tumor-infiltrating lymphocytes (TIL) expressed PD-1, while one third to half of CD8+ TIL co-expressed PD-1 and CTLA-4. Double-positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single-positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two-thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T cell function. When used in combination with GVAX vaccination (consisting of GM-CSF-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T cell activity, while attenuating Treg cell suppression.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4db19bc553bf328b246c8ebe80f51cbba76934ee

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Citations in the corpus

T Cell Dysfunction in Cancer (2018, background): “CTLA-4 blockade has also been suggested to target regulatory T cells by either functional inhibition or depletion of this subset (Duraiswamy et al., 2013; Simpson et al., 2013).”
Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction (2013, unknown): “PD-1+CTLA-4 [116], PD-1+LAG-3 [103], PD-1+TIM-3 [104,117], or PD-1+LAG-3+CTLA-4 [118] may be required in some settings for rescue of T cell function and/or effective T cell-mediated cancer regression.”
CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation (2017, background): “The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade (2015, background): “Because preclinical studies have shown improved in vivo responses when vaccines are combined with both PD-1 and CTLA-4 blockade (39), combiningmultiple immune checkpoint inhibitors with STINGVAX is also a valid clinical strategy.”
Cholesterol induces CD8+ T-cell exhaustion in the tumor microenvironment (2019, unknown): “, the combination of anti-PD-1 with anti-CTLA-4 (Buchbinder and Desai, 2016; Duraiswamy et al., 2013; Dyck and Mills, 2017), anti-PD-1 with anti-TIM-3 (Sakuishi et al.”
Oncology meets immunology: the cancer-immunity cycle. (2013, background): “…that merit serious consideration include anti-PD-L1 or anti-PD-1 with vaccination, especially if it becomes possible to monitor a patient’s T cell profile to distinguish individuals who have generated suboptimal T cell responses to their cancers (Duraiswamy et al., 2013; Ge et al., 2013).”