Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm Review article Role of tumor-in ltrating lymphocytes in patients with solid tumors: Can a fi drop dig a stone? Giuseppe Badalamenti a1 , , Daniele Fanale a1 , , Lorena Incorvaia a1 , , Nadia Barraco a , Angela Listì a , Rossella Maragliano a , Bruno Vincenzi b , Valentina Calò a , Juan Lucio Iovanna c , Viviana Bazan a2 , , Antonio Russo a, ⁎ ,2 a Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy b Medical Oncology Department, University Campus Bio-Medico, 00128 Rome, Italy c Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, Marseille F-13009, France ARTICLE INFO Keywords: Immune suppression Immunotherapy PD-1 PD-L1 Predictive signi cance fi Prognosis Tumor immunology Tumor-in ltrating lymphocytes (TILs) fi Tumor microenvironment ABSTRACT In recent years, multiple strategies for eliciting anti-tumor immunity have been developed in di erent clinical ff studies. Currently, immunotherapy was clinically validated as e ective treatment option for many tumors such ff as melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Some surface receptors of immune cells, called immune checkpoint receptors, may inhibit activity of proin ammatory lymphocytes, fol- fl lowing binding with speci c ligands. Cancer cells exploit these mechanisms to inactivate tumor-in ltrating fi fi lymphocytes (TILs) to escape from immunosurveillance. Among the di erent tumor-in ltrating immune cell ff fi populations, including leucocytes, macrophages, dendritic cells and mast cells, TILs are considered a selected population of T-cells with a higher speci c immunological reactivity against tumor cells than the non-in ltrating fi fi lymphocytes. In this review we will discuss the promising role of TILs as biomarkers re ecting the immune fl response to the tumor, describing their potential ability to predict the prognosis and clinical outcome of im- munotherapy in some solid tumors. 1. Introduction In recent years, multiple strategies for eliciting and enhancing anti- tumor immunity have been developed and evaluated in di erent clin- ff ical studies . Currently, immunotherapy was clinically validated as [1,2] an e ective treatment option for many tumors such as melanoma, non- ff small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) . [35] – Some surface receptors of immune cells, called immune checkpoint receptors, may inhibit activity of killer and pro-in ammatory lympho- fl cytes, following binding with speci c ligands . Cancer cells exploit fi [6] these mechanisms to inactivate tumor-in ltrating lymphocytes (TILs) in fi order to escape from immunosurveillance and survive . Three [7,8] signals are required for T cell activation: i) the interaction between tumor-associated antigens exhibited by major histocompatibility com- plex (MHC) and T-cell receptor (TCR) ; ii) the interaction between [9] receptors on T cells and co-stimulatory molecules on antigen-presenting cells (APCs) ; iii) the release of in ammatory cytokines such as IL-12 [9] fl [10]. The binding of the Programmed Death 1 (PD-1) receptor, mainly expressed on the surface of T cells, to the PD-1 receptor ligands (PD-L1 and PD-L2), expressed on tumor cells, represses the T cell activation signal triggered by binding between MHC and TCR, by inducing T cell apoptosis, resulting in inhibition of their ability to target cancer cells. Therefore, an increase in expression levels of PD-1/PD-L1 may be de- tected in many tumors with poor prognosis . Likewise, also the [11] cytotoxic T lymphocyte-associated protein 4 (CTLA-4), has been shown to suppress T cell activation . Monoclonal antibodies (mAbs) tar- [12] geting mainly PD-1/PD-L1 and CTLA-4 were recently developed for cancer immunotherapy, showing a signi cant success in clinical prac- fi tice . The checkpoint blockade has been shown to act by acti- [12 15] – vating directly cancer-speci c T cells of the immune system in order to fi eradicate tumor. However, many others immune checkpoints are to date known and some of them could be involved in immune attack against cancer . [6,16] Among the di erent tumor-in ltrating immune cell populations, ff fi including leucocytes, macrophages, dendritic cells and mast cells, TILs https://doi.org/10.1016/j.cellimm.2018.01.013 Received 14 October 2017; Received in revised form 30 December 2017; Accepted 19 January 2018 ⁎ Corresponding author at: Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy. 1 Giuseppe Badalamenti, Daniele Fanale and Lorena Incorvaia contributed equally to this work. 2 Antonio Russo and Viviana Bazan are both co-last authors. E-mail address: antonio.russo@usa.net (A. Russo). Cellular Immunology xxx (xxxx) xxx–xxx 0008-8749/ © 2018 Published by Elsevier Inc. Please cite this article as: Badalamenti, G., Cellular Immunology (2018), https://doi.org/10.1016/j.cellimm.2018.01.013