PPARγ inhibition boosts efficacy of PD-L1 Checkpoint Blockade Immunotherapy against Murine Melanoma in a sexually dimorphic manner

Wu, Bogang; Sun, Xiujie; Yuan, Bin; Ge, Fei; Gupta, Harshita; Chiang, Huai-Chin; Li, Jingwei; Hu, Yanfen; Curiel, Tyler J.; Li, Rong

doi:10.7150/ijbs.42966

Cited by 14 publications

(11 citation statements)

References 38 publications

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“…The activation of PPAR-γ displays a contradictory effect in immunotherapies equally. According to Wu, B., et al., the inactivation of PPAR-γ boosts the efficacy of αPD-L1 and αPD-1 antibodies in the treatment against murine mammary tumors ( 53 ). The activation of PPAR-γ in turn suppresses the expression and secretion of inflammatory factors, pro-inflammatory chemokines, which may reprogram the immune microenvironment of cancer to be less “inflamed”, consequently enabling resistance of cancer cells to immune-directed therapies ( 54 ).…”

Section: Functions Of Ppar-γmentioning

confidence: 99%

PPAR-γ Modulators as Current and Potential Cancer Treatments

Chi

Wang

et al. 2021

Front. Oncol.

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Worldwide, cancer has become one of the leading causes of mortality. Peroxisome Proliferator-Activated Receptors (PPARs) is a family of critical sensors of lipids as well as regulators of diverse metabolic pathways. They are also equipped with the capability to promote eNOS activation, regulate immunity and inflammation response. Aside from the established properties, emerging discoveries are also made in PPAR’s functions in the cancer field. All considerations are given, there exists great potential in PPAR modulators which may hold in the management of cancers. In particular, PPAR-γ, the most expressed subtype in adipose tissues with two isoforms of different tissue distribution, has been proven to be able to inhibit cell proliferation, induce cell cycle termination and apoptosis of multiple cancer cells, promote intercellular adhesion, and cripple the inflamed state of tumor microenvironment, both on transcriptional and protein level. However, despite the multi-functionalities, the safety of PPAR-γ modulators is still of clinical concern in terms of dosage, drug interactions, cancer types and stages, etc. This review aims to consolidate the functions of PPAR-γ, the current and potential applications of PPAR-γ modulators, and the challenges in applying PPAR-γ modulators to cancer treatment, in both laboratory and clinical settings. We sincerely hope to provide a comprehensive perspective on the prospect of PPAR-γ applicability in the field of cancer treatment.

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Section: Functions Of Ppar-γmentioning

confidence: 99%

PPAR-γ Modulators as Current and Potential Cancer Treatments

Chi

Wang

et al. 2021

Front. Oncol.

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“…We previously reported sex differences in tumor growth in a PD-L1-dependent manner 23 and we found sex differences in other tumors based on obesity and additional factors. 24 Full understanding of sex differences aside from estrogen effects merit further investigations.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor beta signaling in CD8⁺ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

Yuan

Clark²,

et al. 2021

J Immunother Cancer

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BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERβ that is important for tumor ERβ to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERβ phosphotyrosine switch in regulating host ERβ remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERβ (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2Y55F/Y55F mouse strain and its wild-type (WT) counterpart were compared in various transplant tumor models for their ability to support tumor growth. In addition, flow cytometry-based immunophenotyping was carried out to assess antitumor immunity of WT and mutant hosts. Adoptive transfer of bone marrow and purified CD8+ T cells were performed to identify the host cell type that harbors ERβ-dependent antitumor function. Furthermore, cell signaling assays were conducted to compare T cell receptor (TCR)-initiated signaling cascade in CD8+ T cells of WT and mutant mice. Lastly, the ERβ-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERβ-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERβ function was defined in CD8+ effector T cells. Mechanistically, TCR activation triggers ERβ phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERβ. S-equol facilitates TCR activation that stimulates the ERβ phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERβ phosphotyrosine switch in regulating ERβ-dependent antitumor immunity in CD8+ T cells. Our findings support the development of ERβ agonists including S-equol in combination with ICB immunotherapy for cancer treatment.

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“…In contrast to PPARα which promotes FA catabolism in T lymphocytes for effector functions, 40 PPARγ drives M2 macrophage polarisation and DC tolerisation by triggering FA oxidation. 47 48 Of note, both PPARγ agonist and antagonist have been shown to enhance anti-PD-(L)1 efficacy in cancer models, [49][50][51] which may depend on the CD274 trans-activation effect of PPARγ in different cell types. 49 51 In addition to anti-PD-L1 therapy, we found that cotargeting PPARγ with anti-PD-1 antibody can also counteract the adaptive resistance phenotype (data not shown).…”

Section: Hepatologymentioning

confidence: 99%

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

Xiong

Chan

Zhou

et al. 2023

Gut

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ObjectiveTherapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting.DesignTwo immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481).ResultsAnti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types.ConclusionWe uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.

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PPARγ inhibition boosts efficacy of PD-L1 Checkpoint Blockade Immunotherapy against Murine Melanoma in a sexually dimorphic manner

Cited by 14 publications

References 38 publications

PPAR-γ Modulators as Current and Potential Cancer Treatments

PPAR-γ Modulators as Current and Potential Cancer Treatments

Estrogen receptor beta signaling in CD8⁺ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

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PPARγ inhibition boosts efficacy of PD-L1 Checkpoint Blockade Immunotherapy against Murine Melanoma in a sexually dimorphic manner

Cited by 14 publications

References 38 publications

PPAR-γ Modulators as Current and Potential Cancer Treatments

PPAR-γ Modulators as Current and Potential Cancer Treatments

Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

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Estrogen receptor beta signaling in CD8⁺ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch