Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor immune responses

Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sharma P, Allison JP. Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol. 2020;20(2):75–6.

Article  CAS  PubMed  Google Scholar 

Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM, Taravati K, Tsai K, Nosrati A, Nardo L, Alvarado MD, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest. 2016;126(9):3447–52.

Article  PubMed  PubMed Central  Google Scholar 

Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.

Article  CAS  PubMed  Google Scholar 

Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.

Article  CAS  PubMed  Google Scholar 

Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jansen CS, Prokhnevska N, Kissick HT. The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer. Urol Oncol. 2019;37(8):543–55.

Article  PubMed  Google Scholar 

Zou W, Wolchok JD, Chen L. PD-L1 (B7–H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv324.

Article  Google Scholar 

Bonaventura P, Shekarian T, Alcazer V, Valladeau-Guilemond J, Valsesia-Wittmann S, Amigorena S, Caux C, Depil S. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Galluzzi L, Chan TA, Kroemer G, Wolchok JD, Lopez-Soto A. The hallmarks of successful anticancer immunotherapy. Sci Transl Med. 2018;10(459):eaat7807.

Article  PubMed  Google Scholar 

Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.

Article  CAS  PubMed  Google Scholar 

Scheffold A, Hanna BS, Roeßner P, Demerdash Y, Jebaraj BMC, Lichter P, Stilgenbauer S, Seiffert M. PI3K-δ inhibition influences T-cell populations and anti-tumoral immune function in preclinical models. Blood. 2017;130(Supplement 1):2998–2998.

Google Scholar 

Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407–11.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 2015;128:95–139.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78.

Article  PubMed  PubMed Central  Google Scholar 

Waniczek D, Lorenc Z, Snietura M, Wesecki M, Kopec A, Muc-Wierzgon M. Tumor-associated macrophages and regulatory T cells infiltration and the clinical outcome in colorectal cancer. Arch Immunol Ther Exp (Warsz). 2017;65(5):445–54.

Article  CAS  PubMed  Google Scholar 

Paluskievicz CM, Cao X, Abdi R, Zheng P, Liu Y, Bromberg JS. T regulatory cells and priming the suppressive tumor microenvironment. Front Immunol. 2019;10:2453.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cheng J, Huang Y, Zhang X, Yu Y, Wu S, Jiao J, Tran L, Zhang W, Liu R, Zhang L, et al. TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism. Nat Commun. 2020;11(1):1880.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 2016;6(10):1090–105.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sivaram N, McLaughlin PA, Han HV, Petrenko O, Jiang YP, Ballou LM, Pham K, Liu C, van der Velden AW, Lin RZ. Tumor-intrinsic PIK3CA represses tumor immunogenecity in a model of pancreatic cancer. J Clin Invest. 2019;129(8):3264–76.

Article  PubMed  PubMed Central  Google Scholar 

Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7–24.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu S, Zhang Q, Zhang F, Meng F, Liu S, Zhou R, Wu Q, Li X, Shen L, Huang J, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat Cell Biol. 2019;21(8):1027–40.

Article  CAS  PubMed  Google Scholar 

Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol. 2019;20(9):515–34.

Article  CAS  PubMed  Google Scholar 

Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008;454(7205):776–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang X, Ding J, Meng LH. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies. Acta Pharmacol Sin. 2015;36(10):1170–6.

Article  PubMed  PubMed Central  Google Scholar 

Soond DR, Bjørgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JSH, et al. PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood. 2010;115(11):2203–13.

Article  CAS  PubMed  Google Scholar 

Lim EL, Cugliandolo FM, Rosner DR, Gyori D, Roychoudhuri R, Okkenhaug K. Phosphoinositide 3-kinase delta inhibition promotes antitumor responses but antagonizes checkpoint inhibitors. JCI Insight. 2018;3(11):e120626.

Article  PubMed  PubMed Central  Google Scholar 

Koblish HK, Wang L-C, Hansbury M, Zhang Y, Yang G, Burn T, Waeltz P, Rupar M, Yue E, Douty B, et al. Abstract C103: the combination of PI3kδ-selective inhibition and immunomodulation shows efficacy in solid tumor models. Mol Cancer Ther. 2015;14(12_Supplement_2):C103–C103.

Article  Google Scholar 

Carnevalli LS, Sinclair C, Taylor MA, Gutierrez PM, Langdon S, Coenen-Stass AML, Mooney L, Hughes A, Jarvis L, Staniszewska A, et al. PI3Kalpha/delta inhibition promotes anti-tumor immunity through direct enhancement of effector CD8(+) T-cell activity. J Immunother Cancer. 2018;6(1):158.

Article  PubMed  PubMed Central  Google Scholar 

De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature. 2016;539(7629):443–7.

Article  PubMed  PubMed Central  Google Scholar 

Kaneda MM, Cappello P, Nguyen AV, Ralainirina N, Hardamon CR, Foubert P, Schmid MC, Sun P, Mose E, Bouvet M, et al. Macrophage PI3Kgamma drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 2016;6(8):870–85.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Carnevalli LS, Taylor MA, King M, Coenen-Stass AML, Hughes AM, Bell S, Proia TA, Wang Y, Ramos-Montoya A, Wali N, et al. Macrophage activation status rather than repolarization is associated with enhanced checkpoint activity in combination with PI3Kgamma inhibition. Mol Cancer Ther. 2021;20(6):1080–91.

Article  CAS  PubMed  Google Scholar 

Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, et al. PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and anti-PD1 responses. Clin Cancer Res. 2017;23(13):3371–84.

Article  CAS  PubMed  Google Scholar 

Markham A. Copanlisib: first global approval. Drugs. 2017;77(18):2057–62.

Article  CAS  PubMed  Google Scholar 

Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878.

Article  PubMed 

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