Established T Cell–Inflamed Tumors Rejected after Adaptive Resistance Was Reversed by Combination STING Activation and PD-1 Pathway Blockade

Abstract

Patients with head and neck squamous cell carcinoma harbor T-cell inflamed and non-T-cell inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through pattern-recognition receptors such as the stimulator of interferon (IFN) genes (STING) receptor may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T-cell inflamed (MOC1), but not non-T-cell inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP,RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1–pathway components in vivo. Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1-pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity.

Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ

“…When injected into wild-type B6 mice, MOC1 cells generate T-cell inflamed tumors capable of inducing immunologic memory and MOC2 cells generate non-T-cell inflamed tumors that do not generate immunology memory (24,28). Compared to naïve spleen and normal oral mucosa, spleens and tumors in MOC1 tumor-bearing mice demonstrated robust accumulation of myeloid cells (Figure 1A, left panels).…”

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

“…We explored this possibility in mice bearing MOC1 tumors, which typically induce immune responses and respond to immunotherapies, whereas MOC2 tumors, which are aggressive, do not typically induce immune responses and do not respond well to immunotherapies (16, 17, 22, 28). In MOC1-bearing mice, cisplatin (5 mg/kg/week) and anti–PD-L1 did not delay tumor growth when used alone but provided a significant tumor growth delay and prolonged survival when used concurrently (Fig.…”

“…Human cell lines were maintained in MEM or DMEM with 1% penicillin/streptomycin, 1% glutamine, and 10% FBS. Mouse oral cancer (MOC) 1 and 2 cell lines were obtained from Dr. R. Uppaluri in 2014 and were authenticated by exome sequencing and maintained as previously described (16, 17). All cell lines were stored in liquid nitrogen and cultured for no longer than 6 months or 20 passages before use.…”

Syngeneic Mouse Models of Oral Cancer Are Effectively Targeted by Anti–CD44-Based NIR-PIT

“…MOC models are carcinogen-induced, fully syngeneic on a C57BL/6 genetic background, and consist of cell lines with genetic alterations that mirror human OSCC (28, 32, 33, 36). Cells treated with NIR-PIT undergo rapid volume expansion leading to rupture of the cell membrane and extrusion of cell contents into the extracellular space (Figure 1, Video S1 and S2), also known as, an immunogenic cell death (ICD) in contrast to most other treatments that result in apoptosis (26, 37–39).…”