基于肿瘤浸润淋巴细胞治疗卵巢癌的研究进展

Advances in tumor-infiltrating lymphocyte therapy for ovarian cancer

摘要

卵巢癌(ovarian cancer, OVCA)是严重威胁女性的身体健康和生命安全的妇科恶性肿瘤,尽管近年来现代医学和外科手术取得了显著进步,Ⅲ期和Ⅳ期OVCA患者的5年生存率仅有27%和13%。肿瘤浸润淋巴细胞(tumor infiltrating lymphocytes,TIL)是一类浸润于肿瘤实质或间质中的免疫细胞,与非肿瘤浸润性淋巴细胞相比,TIL具有更高水平的抗肿瘤免疫应答能力。TIL疗法是创新的细胞疗法,其制剂由患者自体肿瘤中TIL筛选和扩增而来,具有强大的抗肿瘤活性和较低的脱靶毒性。研究发现,TIL大量浸润与OVCA患者接受临床治疗后更好的预后相关,早期临床试验亦证实了TIL疗法治疗OVCA的可行性。本文主要就卵巢肿瘤微环境中关键TIL、TIL疗法的临床转化以及临床应用可能面临的挑战与优化策略进行综述,以期为TIL疗法治疗OVCA提供科学参考。

Abstract

Ovarian cancer (OVCA) is a gynecological malignancy that poses a serious threat to women's health and life. Despite significant advances in modern medicine and surgery in recent years, the five-year survival rates for patients with stages Ⅲ and Ⅳ OVCA are only 27% and 13%, respectively. Tumor-infiltrating lymphocytes (TILs) are a type of immune cell that infiltrate the tumor parenchyma or stroma. Compared to non-tumor-infiltrating lymphocytes, TILs exhibit a stronger ability for antitumor immune responses. TIL therapy is an innovative cell-based treatment in which the therapeutic preparation is derived from the selection and expansion of autologous TILs obtained from the patient's own tumor tissue, offering potent antitumor activity and low off-target toxicity. Studies have shown that extensive TIL infiltration is associated with improved prognosis in OVCA patients after clinical treatment, and early-phase clinical trials have also demonstrated the feasibility of TIL therapy for OVCA. This review focuses on key TILs within the ovarian tumor microenvironment, the clinical translation of TIL therapy, and the potential challenges and optimization strategies for its clinical application, aiming to provide a scientific reference for TIL-based treatment of OVCA.

关键词

卵巢癌 / 免疫治疗 / 肿瘤浸润淋巴细胞 / 过继性免疫细胞疗法 / 肿瘤微环境

Key words

ovarian cancer / immunotherapy / tumor-infiltrating lymphocytes / adoptive cell therapy / tumor microenvironment

[1] COLOMBO N, SESSA C, DU BOIS A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[J]. Ann Oncol, 2019, 30(5): 672-705.
[2] WANG Y, WANG Z, ZHANG ZH, et al. Burden of ovarian cancer in China from 1990 to 2030: a systematic analysis and comparison with the global level[J]. Front Public Health, 2023, 11: 1136596.
[3] SIDERIS M, MENON U, MANCHANDA R. Screening and prevention of ovarian cancer[J]. Med J Aust, 2024, 220(5): 264-274.
[4] KONSTANTINOPOULOS PA, MATULONIS UA. Clinical and translational advances in ovarian cancer therapy[J]. Nat Cancer, 2023, 4(9): 1239-1257.
[5] ZILBERG C, FERGUSON AL, LYONS JG, et al. The tumor immune microenvironment in primary cutaneous melanoma[J]. Arch Dermatol Res, 2025, 317(1): 273.
[6] SARNAIK AA, HAMID O, KHUSHALANI NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma[J]. J Clin Oncol, 2021, 39(24): 2656-2666.
[7] GHISONI E, BENEDETTI F, MINASYAN A, et al. Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer[J]. Cancer Cell, 2025, 43(8): 1568-1586. e10.
[8] ZHANG L, CONEJO-GARCIA JR, KATSAROS D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer[J]. N Engl J Med, 2003, 348(3): 203-213.
[9] BREDEL D, TIHIC E, MOURAUD S, et al. Immune checkpoints are predominantly co-expressed by clonally expanded CD4⁺FoxP3⁺ intratumoral T-cells in primary human cancers[J]. J Exp Clin Cancer Res, 2023, 42(1): 333.
[10] LOPEZ DE RODAS M, NAGINENI V, RAVI A, et al. Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer[J]. J Immunother Cancer, 2022, 10(6): e004440.
[11] WONG PF, WEI W, SMITHY JW, et al. Multiplex quantitative analysis of tumor-infiltrating lymphocytes and immunotherapy outcome in metastatic melanoma[J]. Clin Cancer Res, 2019, 25(8): 2442-2449.
[12] TAY RE, RICHARDSON EK, TOH HC. Revisiting the role of CD4⁺ T cells in cancer immunotherapy-new insights into old paradigms[J]. Cancer Gene Ther, 2021, 28(1-2): 5-17.
[13] RUDENSKY AY. Regulatory T cells and Foxp3[J]. Immunol Rev, 2011, 241(1): 260-268.
[14] MYOJIN Y, BABAEI S, TREHAN R, et al. Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab[J]. Gut, 2025, 74(6): 983-995.
[15] FRIDMAN WH, MEYLAN M, PETITPREZ F, et al. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome[J]. Nat Rev Clin Oncol, 2022, 19(7): 441-457.
[16] LUNDGREN S, BERNTSSON J, NODIN B, et al. Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer[J]. J Ovarian Res, 2016, 9: 21.
[17] KASIKOVA L, RAKOVA J, HENSLER M, et al. Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer[J]. Nat Commun, 2024, 15(1): 2528.
[18] CÓZAR B, GREPPI M, CARPENTIER S, et al. Tumor-infiltrating natural killer cells[J]. Cancer Discov, 2021, 11(1): 34-44.
[19] LOPES N, VIVIER E, NARNI-MANCINELLI E. Natural killer cells and type 1 innate lymphoid cells in cancer[J]. Semin Immunol, 2023, 66: 101709.
[20] SLATTERY K, YAO CH, MYLOD E, et al. Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer[J]. Sci Immunol, 2025, 10(107): eadr4795.
[21] AOKI Y, TAKAKUWA K, KODAMA S, et al. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer[J]. Cancer Res, 1991, 51(7): 1934-1939.
[22] FUJITA K, IKARASHI H, TAKAKUWA K, et al. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes[J]. Clin Cancer Res, 1995, 1(5): 501-507.
[23] CHESNEY J, LEWIS KD, KLUGER H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study[J]. J Immunother Cancer, 2022, 10(12): e005755.
[24] AI LY, XU AT, XU J. Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond[M]//Regulation of Cancer Immune Checkpoints. Singapore: Springer Singapore, 2020: 33-59.
[25] BAŞ Y, KOÇ N, HELVAC? K, et al. Clinical and pathological significance of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression in high grade serous ovarian cancer[J]. Transl Oncol, 2021, 14(2): 100994.
[26] CHENG LY, CHEN LJ, SHI Y, et al. Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison[J]. Mol Cancer, 2024, 23(1): 77.
[27] GANGAEV A, ROZEMAN EA, ROHAAN MW, et al. Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response[J]. Proc Natl Acad Sci USA, 2021, 118(43): e2102849118.
[28] MULLINAX JE, HALL M, PRABHAKARAN S, et al. Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma[J]. Front Oncol, 2018, 8: 44.
[29] 于雅鑫, 王晓丽, 张大奎, 等. 奥拉帕尼衍生物作为PARP-1抑制剂的设计及合成[J]. 中国医药导刊, 2025, 27(4): 412-418.
[30] LI SY, WANG LL, WANG YY, et al. The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment[J]. J Hematol Oncol, 2022, 15(1): 147.
[31] BARADÁCS I, TEUTSCH B, VÁRADI A, et al. PARP inhibitor era in ovarian cancer treatment: a systematic review and meta-analysis of randomized controlled trials[J]. J Ovarian Res, 2024, 17(1): 53.
[32] STANGE C, DREYER TF, RIEDEL M, et al. PARP inhibitor-induced anti-tumour chemokine response is suppressed by dipeptidyl peptidase 4 (DPP4) in ovarian cancer[J]. Br J Cancer, 2025, 133(4): 582-593.
[33] SANTOIEMMA PP, POWELL DJ Jr. Tumor infiltrating lymphocytes in ovarian cancer[J]. Cancer Biol Ther, 2015, 16(6): 807-820.
[34] RAHMAN MM, MCFADDEN G. Oncolytic viruses: newest frontier for cancer immunotherapy[J]. Cancers (Basel), 2021, 13(21): 5452.
[35] SANTOS JM, HEINIÖ C, CERVERA-CARRASCON V, et al. Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity[J]. J Immunother Cancer, 2020, 8(1): e000188.
[36] QUIXABEIRA DA, JIROVEC E, PAKOLA S, et al. Improving the cytotoxic response of tumor-infiltrating lymphocytes towards advanced stage ovarian cancer with an oncolytic adenovirus expressing a human vIL-2 cytokine[J]. Cancer Gene Ther, 2023, 30(11): 1543-1553.
[37] GE CX, YANG XL, XIN JX, et al. Recent advances in antitumor dendritic cell vaccines[J]. Cancer Biother Radiopharm, 2023, 38(7): 450-457.
[38] TANYI JL, BOBISSE S, OPHIR E, et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer[J]. Sci Transl Med, 2018, 10(436): eaao5931.
[39] FUCIKOVA J, HENSLER M, KASIKOVA L, et al. An autologous dendritic cell vaccine promotes anticancer immunity in patients with ovarian cancer with low mutational burden and cold tumors[J]. Clin Cancer Res, 2022, 28(14): 3053-3065.
[40] WU B, ZHANG B, LI BW, et al. Cold and hot tumors: from molecular mechanisms to targeted therapy[J]. Signal Transduct Target Ther, 2024, 9(1): 274.
[41] ABREU MM, CHOCRON AF, SMADJA DM. From cold to hot: mechanisms of hyperthermia in modulating tumor immunology for enhanced immunotherapy[J]. Front Immunol, 2025, 16: 1487296.
[42] ZHAO J, WANG ZM, TIAN YY, et al. T cell exhaustion and senescence for ovarian cancer immunotherapy[J]. Semin Cancer Biol, 2024, 104-105: 1-15.
[43] KRISHNA S, LOWERY FJ, COPELAND AR, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer[J]. Science, 2020, 370(6522): 1328-1334.
[44] RAFIQUL ISLAM SM, MAEDA T, TAMAOKI N, et al. Reprogramming of tumor-reactive tumor-infiltrating lymphocytes to human-induced pluripotent stem cells[J]. Cancer Res Commun, 2023, 3(5): 917-932.
[45] ZHANG L, MORGAN RA, BEANE JD, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma[J]. Clin Cancer Res, 2015, 21(10): 2278-2288.
[46] SHEN J, ZOU ZZ, GUO JY, et al. An engineered concealed IL-15-R elicits tumor-specific CD8⁺ T cell responses through PD-1-Cis delivery[J]. J Exp Med, 2022, 219(12): e20220745.