## 2 Antitumor Immunity and Tumor Immune Escape  
Our immune system can respond to infections and exogenous stimuli through a non-specific and quick response, the innate immunity, and a subsequently activated antigen-specific response that mediates the immune memory, called adaptative immunity [11]. The activation of antitumor immunity is a complex process, in which several cell and lymphocyte populations are involved. The uncontrolled proliferation of cancer cells causes a high tumor mutational burden firstly leading to the activation of innate immunity. In particular, natural killer (NK) cells target cancer cells, causing their apoptosis and a release of tumor-associated antigens (TAAs), which are tumor proteins that the immune system recognizes as non-self. TAAs can be distinguished in non-mutated self-antigens and major histocompatibility complex (MHC)-I-restricted or MHC-II-restricted neoantigens, which arises as the result of non-synonymous somatic mutations [12; 13; 14; 15; 16]. Self-antigens are non-mutated proteins aberrantly expressed or overexpressed in tumor cells. Despite their contribution to tumor immunity, the primary targets of many antitumor immune responses are tumor-specific neoantigen peptides that are the result of somatic mutations in cancer genomes [13; 14; 17; 18; 19; 20; 21; 22; 23]. These neoantigens (mutated proteins), released by cancer cells in the tumor microenvironment (TME), are subsequently captured by antigen-presenting cells (APCs). The APCs then migrate to lymph nodes where they present neoantigens to T-cell receptors (TCR) on immature T lymphocytes through the MHC. However, antigen stimulation alone is not enough to activate naive T lymphocytes, and an additional co-stimulatory signal is required. Indeed, T cells become fully activated after the binding between CD28 on T cells and CD80 or CD86 (named also B7-1 and B7-2, respectively) on APCs (priming phase) (Figure 1A). Upon returning from the lymph nodes to the tumor site, activated T cells recognize TAAs on the tumor cells and attack them via perforin and granzyme (effector phase) (Figure 1A) [11]. Although the immune system is able to recognize and destroy cancer cells, malignant cells can develop different mechanisms aimed at evading the host's immune control, by reducing MHC complex expression on APCs or inhibiting the immune response (immune checkpoint molecules) [24; 25]. Among these molecules, the most relevant are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and its ligand (PD-L1), and lymphocyte-activation gene-3 (LAG-3). The fundamental role of these molecules is to counterbalance lymphocyte activation in physiological conditions, in order to avoid unnecessary tissue damage, chronic inflammation, and uncontrolled lymphocytic proliferation. In detail, CTLA4 exerts its activity solely within lymph nodes and is expressed constitutively on regulatory T cells (T\({}_{\text{reg}}\)) and transiently on several T cells in the early priming phase [26]. B7-1 and B7-2 (the molecules responsible for the co-stimulatory signal) also bind to CTLA4, with an affinity 10 times as strong as it is for CD28. As a consequence, the binding to CTLA4 is preferred over CD28, leading to the inhibition of T cells activation. CTLA4 acts as a brake on the activation and proliferation of T cells. This, in physiological conditions, prevents excessive immune responses by limiting unnecessary T cells activity, but it impairs anticancer immunity by hindering cancer antigens recognition (Figure 1B). PD-1 is an immune co-inhibitory receptor expressed on T cells and on several other immune cells [26]. On T lymphocytes, PD-1 prevents antigen-specific activation through interactions with its ligands PD-L1 (expressed in dendritic cells and in cells from several other tissues) and PD-L2 (expressed only in dendritic cells). PD-1 is expressed selectively on T cells at the late activation stage, and its expression is particularly strong in effector T cells in peripheral tissues.