Enhanced Tumor Control with Combination mTOR and PD-L1 Inhibition in Syngeneic Oral Cavity Cancers

Abstract

Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti-PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFNγ production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which was stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFNγ production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T cell, and not NK cell, -dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell–mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFNγ or PD-L1 mAb treatment–associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. This data conflicts with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggests that this treatment combination deserves careful evaluation in the clinical setting.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…Whilst these studies build on previous pre-clinical observations of combinatorial benefit between the mTORC1 inhibitor rapamycin and α-PD-L1 immune checkpoint blockade in a syngeneic oral cavity cancer model, 12 our results provide novel insight to the mechanisms underlying such potential synergy and extend these findings to a clinical mTOR kinase inhibitor for the first time. Whilst we observed that αCTLA-4 immune-checkpoint blockade was efficient at recruiting/expanding CD8 + T-effector populations in tumours, these cells retained a somewhat exhausted phenotype (Fig.…”

“…These results contribute to a growing body of evidence that suggest mTOR inhibition can promote favourable immune effects. For instance, mTOR inhibitors have been shown to synergize with tumour vaccines, 41,42 in addition to αPD-L1 immune checkpoint blockade, 12 suggesting that combination of mTOR inhibitors and immune potentiating therapies could represent a broadly applicable therapeutic approach.…”

“…12,13 Interpretation of these questions has been obscured by the use of mTORC1-targeting rapalogues, that deliver incomplete pathway inhibition, 14 or by non-clinical quality mTOR kinase inhibitor compounds which may possess off-target activity at therapeutically relevant doses. 15 To systematically address the immunological impact of acute mTOR inhibition in cancer, we investigated the impact of the clinical dual mTORC1/2 kinase inhibitor vistusertib (AZD2014) in the context of anti-tumour immunotherapy.…”

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).…”

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

“…CD8 + T cells and NK cells were depleted in a subset of mice by intraperitoneal injection of depleting antibodies (clones listed above) at 200 mcg twice weekly as previously described and validated (22). …”