The role of tumor-infiltrating lymphocytes in triple-negative breast cancer and the research progress of adoptive cell therapy

Abstract

The treatment outcome of breast cancer is closely related to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Triple-negative breast cancer (TNBC) lacking ER, PR, and HER2 expression has limited treatment options and a poor prognosis. Tumor-infiltrating lymphocytes (TILs) play a role in promoting or resisting tumors by affecting the tumor microenvironment and are known as key regulators in breast cancer progression. However, treatments for TNBC (e.g., surgery, chemotherapy and radiotherapy) have non-satisfaction's curative effect so far. This article reviews the role of different types of TILs in TNBC and the research progress of adoptive cell therapy, aiming to provide new therapeutic approaches for TNBC.

Keywords: adoptive cell therapy (ACT); breast cancer; solid tumor; triple-negative breast cancer (TNBC); tumor-infiltrating lymphocytes (TILs).

Figure 1

Functional subsets of CD4⁺ T cells and the role of other lymphocytes in immunity. Naïve CD4+ T cells differentiate into five subtypes: Th1, Th2, Th17, Treg, and Tfh, through the corresponding STAT pathway and cytokine induction. IFN-γ and IL-4 produced by anti-tumor Th1 cells and tumor-promoting Th2 cells not only restrict each other to maintain balance but also jointly inhibit the differentiation of Th17 cells. Th17 cells have a dual role—according to the different TMEs to secrete CCL2 and CCL20 to enhance immunosuppression or secrete CXCL1 to directly act on the surface of tumor cells to promote tumor progression. CXCL13 secreted by CD8⁺ T cells not only recruits Tfh but also participates in B cell differentiation together with IL-21. Differentiated and mature long-lived plasma cells release corresponding antibodies and upregulate NK cells to kill tumor cells. CD8⁺ T cells differentiate into tissue-resident memory CD8⁺ T cells to recognize E-cadherin on the surface of tumor cells and inhibit tumor growth. Breg and Treg cells are both tumor-promoting cells. Breg cells release IL-10 and recognize soluble PD-L1, which jointly induce Treg cell differentiation, suppress immune responses, and build a microenvironment which is conducive to tumor growth.

Figure 2

Production process of ACT. (A) Preparation of CAR-T cells for CAR-T-cell therapy: peripheral blood mononuclear cells of the patients are extracted by leukapheresis, washed to remove impurities, and specific T cells are isolated using magnetic-bead separation. After activation, viral or non-viral vectors are used to transduce T cells for CAR expression on the cell surface. The CAR-T cells are then expanded to the target dose, and the effectiveness and safety of the cells are checked. CAR-T cells that pass quality control are reinfused into the patients. (B) The preparation of CAR-NK cells for ACT is similar to the preparation of CAR-T cells. However, CAR-NK cells exert a more powerful and specific tumor targeting capacity by expressing NKG2D, CD266, and other NK cell surface receptors. (C) Preparation of TCR-T cells for ACT: T cells are extracted from the peripheral blood of the patients, followed by delivering specific TCR genes to the T cells through a viral or non-viral delivery system, expanding the TCR-T cells in large quantities, and conducting quality control for the cell culture. The qualified TCR-T cultured cells are reinfused into the patients. (D) Preparation of TILs for ACT: Tumor tissues collected from the patients are cut into many small pieces and cultured in a 24-well plate for two to three weeks with medium containing a high concentration of IL-2, followed by selecting TILs which are capable of secreting IFN-γ and culturing them to a therapeutic dose before infusing the cells into patients.