Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Chaoul, Nada; Fayolle, Catherine; Desrues, Belinda; Oberkampf, Marine; Tang, Alexandre; Ladant, Daniel; Leclerc, Claude

doi:10.1158/0008-5472.can-15-0454

Cited by 49 publications

(40 citation statements)

References 49 publications

(82 reference statements)

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“…Given that mTORC2 inhibition is required for the development of memory T cells (34), it is possible that dosing and duration of rapamycin treatment are factors affecting whether immune responses are enhanced or inhibited. These data, along with ours demonstrating enhanced antitumor immunity with combination rapamycin and PD-L1 mAb treatment, contrast with a report showing impairment of an HPV-peptide based therapeutic vaccine after rapamycin treatment (35). Here, regression of a subset of HPV-E7 + TC-1 tumors following administration of a therapeutic vaccine was reversed following administration of rapamycin at doses similar to our experiments.…”

Section: Discussioncontrasting

confidence: 99%

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

Moore

Cash

Caruso

et al. 2016

Cancer Immunology Research

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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.

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Section: Discussioncontrasting

confidence: 99%

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

Moore

Cash

Caruso

et al. 2016

Cancer Immunology Research

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“…Indeed, clinical application of mTOR-dependent autophagy inducers, such as rapamycin, must take into account their effect on mTOR inhibition because cellular functions besides autophagy are potentially disturbed79. For example, Chaoul N et al 80. reported that rapamycin affects cancer vaccine therapy by impairing antitumour CD8+ T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway

Chen

et al. 2016

Sci Rep

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Trehalose is a natural disaccharide that is found in a diverse range of organisms but not in mammals. Autophagy is a process which mediates the sequestration, lysosomal delivery and degradation of proteins and organelles. Studies have shown that trehalose exerts beneficial effects through inducing autophagy in mammalian cells. However, whether trehalose or other saccharides can activate autophagy in keratinocytes is unknown. Here, we found that trehalose treatment increased the LC3-I to LC3-II conversion, acridine orange-stained vacuoles and GFP-LC3B (LC3B protein tagged with green fluorescent protein) puncta in the HaCaT human keratinocyte cell line, indicating autophagy induction. Trehalose-induced autophagy was also observed in primary keratinocytes and the A431 epidermal cancer cell line. mTOR signalling was not affected by trehalose treatment, suggesting that trehalose induced autophagy through an mTOR-independent pathway. mTOR-independent autophagy induction was also observed in HaCaT and HeLa cells treated with sucrose or raffinose but not in glucose, maltose or sorbitol treated HaCaT cells, indicating that autophagy induction was not a general property of saccharides. Finally, although trehalose treatment had an inhibitory effect on cell proliferation, it had a cytoprotective effect on cells exposed to UVB radiation. Our study provides new insight into the saccharide-mediated regulation of autophagy in keratinocytes.

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“…Given the unusual nature of the suppressed immune-microenvironment within a tumour, and the pleiotropic impacts of mTOR inhibitors on distinct immune cell subsets, it remains unclear whether mTOR inhibition will suppress anti-tumour immunity, 11 or whether it will potentiate anti-tumour responses. 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

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Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Cited by 49 publications

References 49 publications

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

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

Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway

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

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