How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Abstract

In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed.

Platelet‐to‐lymphocyte ratio predicts the prognosis of patients with non‐small cell lung cancer treated with surgery and postoperative adjuvant chemotherapy

“…Lymphocytes induce tumor cell apoptosis, and their abundance has been shown to be inversely proportional to tumor growth and invasion 18. A reduction in lymphocyte numbers would undoubtedly reduce the host anti‐tumor immune response and promote the metastatic potential of the tumor.…”

Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model

“…Th1 produces IL-2 which further promotes proliferation of effector T cells. CD 4 + T cells (Th1) can kill cancer cell directly, for example, through FAS- or TRAIL-dependent pathway [22–25], while CD 8 + T cell is more effective in killing cancer cells [26]. Cancer cells suppress the functions of effector T cells by producing immunosuppressor cytokines TGF- β , IL-6, CCL2 and IL-10 [27].…”

Case of Thrombosis of Rare Localization in a Cancer Patient with Combined form of Thrombophilia

“…A powerful fibrin barrier is formed due to distortion of the processes of permanent stimulation of fibrinogenesis and concomitant fibrinolysis in the tumor zone [5,6]. From the side of tumor cells, the initiating effect on the components of the hemostasis system and the process of fibrin formation is mediated by macrophages present in the tumor zone, whose reaction to malignant cells is expressed by increased production of proinflammatory cytokines, such as TNFα, IL-1, IL-6, IL-8 and other active molecules [7,8]. In the focus of tumor growth, the protective role of fibrin is distorted, and transformed cells use fibrin mesh as a mechanical barrier from the cells of the immune system.…”