GPR183-mediated activation of PI3K is a potential biomarker for immunotherapy in lung cancer

Abstract

Background: As one of commonly used immune checkpoint inhibition therapies, PD1 monoclonal antibodies exhibit a promising cancer immunotherapy approach. However, their efficacy on tumour immunity needs to be augment, as large numbers of patients poorly respond to the treatment or suffer from recurrence in clinical. Although pan-PI3K is involved in the performance of PD1 on T cell immunity, the study for mechanisms of PI3K subunits involved in could be helpful for proposing a potential treatment strategy for lung cancer that combines anti-PD1 treatment with PI3Kγ inhibitor.

Materials & answers: Alterations of CD4⁺ and CD8⁺ T cell subpopulations in 11 types of peripheral blood mononuclear cells with healthy subjects and cancer patients were examined. The efficacy of different treatment strategies for lung cancer was then investigated, and the factors affecting the efficacy of anti-PD1 therapy in lung cancer were discussed.

Results: Lung cancer is characterized by widespread variation in T cell subsets, and anti-PD1 treatment is effective against CD4⁺ Tcm, CD4⁺ Tem and CD4⁺ Tn cell subsets. The involvement of PI3K in the effect of anti-PD1 was demonstrated using single-cell RNA sequencing. The PI3Kγ inhibitor CAY10505 was effective against CD4⁺ Tcm and CD4⁺ Tn subsets in lung cancer in vitro but not in pan-cancer therapy, indicating that the therapeutic effect of PI3Kγ on CD4⁺ T cells was lung cancer-specific. G-protein coupled receptor 183 (GPR183) was involved in migration and positioning of immune cells and associated with various immune-related diseases.

Discussion: We explored the regulatory role of GPR183 in the PI3K pathway and T cell subsets and identified potential lipids involved using lipidomics. We found that inhibition of PI3Kγ upregulated CD4⁺ Tcm and CD4⁺ Tn, potentially enhancing the therapeutic efficacy of anti-PD1 antibodies. Combining anti-PD1 treatment with PI3Kγ inhibitor could be a potential treatment strategy for lung cancer.

Keywords

anti-PD1 / lung cancer / PI3Kγ / T cells

References

[1] Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020; 21(9): 3233.

[2] Lowery FJ, Krishna S, Yossef R, et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science. 2022; 375(6583): 877-884.

[3] Deli T, Orosz M, Jakab A. Hormone replacement therapy in cancer survivors—review of the literature. Pathol Oncol Res: POR. 2020; 26(1): 63-78.

[4] Fenis A, Demaria O, Gauthier L, et al. New immune cell engagers for cancer immunotherapy. Nat Rev Immunol. 2024; 24(7): 471-486.

[5] Abbott M, Ustoyev Y. Cancer and the immune system: the history and background of immunotherapy. Semin Oncol Nurs. 2019; 35(5):150923.

[6] Sánchez-Magraner L, Gumuzio J, Miles J, et al. Functional engagement of the PD-1/PD-L1 complex but not PD-L1 expression is highly predictive of patient response to immunotherapy in non-small-cell lung cancer. J Clin Oncol: Official J Am Soc Clin Oncol. 2023; 41(14): 2561-2570.

[7] Dantoing E, Piton N, Salaün M, et al. Anti-PD1/PD-L1 immunotherapy for non-small cell lung cancer with actionable oncogenic driver mutations. Int J Mol Sci. 2021; 22(12): 6288.

[8] Larroquette M, Guegan JP, Besse B, et al. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies. J Immunother Cancer. 2022; 10(5):e003890.

[9] Li H, Wen X, Ren Y, et al. Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions. Mol Cancer. 2024; 23(1): 164.

[10] Noorolyai S, Shajari N, Baghbani E, et al. The relation between PI3K/AKT signalling pathway and cancer. Gene. 2019; 698: 120-128.

[11] Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019; 18(1): 26.

[12] Chaudagar K, Hieromnimon HM, Khurana R, et al. Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer. Clin Cancer Res: Official J Am Assoc Cancer Res. 2023; 29(10): 1952-1968.

[13] Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023; 22(1): 138.

[14] Wang J-F, Wang Y-P, Xie J, et al. Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis. Blood. 2021; 138(9): 806-810.

[15] Sun P, Zhang X, Wang RJ, et al. PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism. J Immunother Cancer. 2021; 9(8):e003093.

[16] Mcritchie BR, Akkaya B. Exhaust the exhausters: targeting regulatory T cells in the tumor microenvironment. Front Immunol. 2022; 13:940052.

[17] Bai Y, Hu M, Chen Z, et al. Single-cell transcriptome analysis reveals RGS1 as a new marker and promoting factor for T-cell exhaustion in multiple cancers. Front Immunol. 2021; 12:767070.

[18] Shah P, Forget MA, Frank ML, et al. Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes. J Immunother Cancer. 2022; 10(2):e003082.

[19] Krijgsman D, De Vries NL, Skovbo A, et al. Characterization of circulating T-, NK-, and NKT cell subsets in patients with colorectal cancer: the peripheral blood immune cell profile. Cancer Immunol Immunother. 2019; 68(6): 1011-1024.

[20] An HJ, Chon HJ, Kim C. Peripheral blood-based biomarkers for immune checkpoint inhibitors. Int J Mol Sci. 2021; 22(17): 9414.

[21] Yang K, Wang X, Song C, et al. The role of lipid metabolic reprogramming in tumor microenvironment. Theranostics. 2023; 13(6): 1774-1808.

[22] Kjær VMS, Daugvilaite V, Stepniewski TM, et al. Migration mediated by the oxysterol receptor GPR183 depends on arrestin coupling but not receptor internalization. Sci Signal. 2023; 16(779):eabl4283.

[23] Chen KY, De Giovanni M, Xu Y, et al. Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes. Cell. 2025; 188(4): 1019-1035.e22.

[24] Li X, Sun W, Xu X, et al. Hepatitis B virus surface antigen drives T cell immunity through non-canonical antigen presentation in mice. Nat Commun. 2025; 16(1): 4591.

[25] Guo X, Nie H, Zhang W, et al. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell. 2025; 43(2): 248-268.e9.

[26] Zhang Y, Chen H, Mo H, et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell. 2021; 39(12): 1578-1593.e8.

[27] Syamsu SA, Faruk M, Smaradania N, et al. PD-1/PD-L1 pathway: current research in breast cancer. Breast Dis. 2024; 43(1): 79-92.

[28] Wu J, Zhao X, Sun Q, et al. Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model. Biomed Pharmacother. 2020; 125:109746.

[29] Beck KM, Yang EJ, Sekhon S, et al. Dupilumab treatment for generalized prurigo nodularis. JAMA Dermatol. 2019; 155(1): 118-120.

[30] Lamarche NM, Hegde S, Park MD, et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature. 2024; 625(7993): 166-174.

[31] Song Y, Bugada L, Li R, et al. Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice. Sci Transl Med. 2022; 14(643):eabl3649.

[32] Shayan G, Srivastava R, Li J, et al. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology. 2017; 6(1):e1261779.

[33] Shi T, Zhang Y, Wang Y, et al. DKK1 promotes tumor immune evasion and impedes anti-PD-1 treatment by inducing immunosuppressive macrophages in gastric cancer. Cancer Immunol Res. 2022; 10(12): 1506-1524.

[34] Kim M, Park J, Bouhaddou M, et al. A protein interaction landscape of breast cancer. Science. 2021; 374(6563):eabf3066.

[35] Vasan N, Razavi P, Johnson JL, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science. 2019; 366(6466): 714-723.

[36] Shi L, Zhu W, Huang Y, et al. Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer. Clin Transl Med. 2022; 12(7):e989.

[37] Juric D, Janku F, Rodón J, et al. Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wild-type estrogen receptor-positive advanced breast cancer: a phase 1b clinical trial. JAMA Oncol. 2019; 5(2):e184475.

[38] André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019; 380(20): 1929-1940.

[39] Albelda SM. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat Rev Clin Oncol. 2024; 21(1): 47-66.

[40] Seung E, Xing Z, Wu L, et al. A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells. Nature. 2022; 603(7900): 328-334.

[41] Kruse B, Buzzai AC, Shridhar N, et al. CD4(+) T cell-induced inflammatory cell death controls immune-evasive tumours. Nature. 2023; 618(7967): 1033-1040.

[42] Liu X, Jiang Y, Song D, et al. Clinical challenges of tissue preparation for spatial transcriptome. Clin Transl Med. 2022; 12(1):e669.

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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.