TO THE EDITOR: We read with great interest the review by Spector and Blackwell, 1 in which the authors highlight the most important mechanisms by which trastuzumab carries out its intracellular and extracellular effects against human epidermal growth factor receptor 2 (HER2)–positive breast cancer cells. The authors identified four direct trastuzumab-mediated cytotoxic effects and an indirect cytotoxic mechanism. The direct mechanisms consist in the blockage of different intracellular transduction signal cascades caused by the interaction between the HER2 and the monoclonal antibody, whereas the indirect mechanismconsistsintheactivationofthehost’sinnateimmunesystem. There is abundant evidence that demonstrates that trastuzumab, through its immunoglobulin G1 humanized Fc portion, 2 is able to act as an autologous antibody3 and activate antibody-dependent cellmediated cytotoxicity by natural killer cells. 4-8 We agree that antibody-dependent cell-mediated cytotoxicity is an intuitive and important immunological mechanism of trastuzumab; however, current findings have clearly demonstrated a pivotal roleoftheadaptiveimmunesystemincancercontrol. Infact, frequently, patients with breast cancer exhibit an HER2 CD8+ T cell immunity. In vivo studies on murine models affected by chemically induced sarcomas demonstrated that the adaptive immune system plays a pivotal role in the tumor-host relationship and is able to maintain neoplasm in a dormancy state. 9 In these models, the innate immune system played a minor role. The finding that the adaptive immune system has a key role in preventing tumor progression is in line with clinical findings carried out in several tumors, 10-12 including breast cancer, 13 where there is a significant correlation between tumorinfiltrating lymphocytes and prognosis. Neoplastic samples obtained from women previously treated with trastuzumab show a significant increase in CD8+ and CD4+ cells, demonstrating that this antibody can activate different mechanisms able to recruit lymphocytes in the tumor site. 7 The cascade by which this antibody elicits a specific adaptive immune response begins with trastuzumab-induced HER2 downmodulation and consequent internalization. HER2/neu protein is then processed and HER2/neu-derived peptides are presented to matched specific lymphocytes on major histocompatibility complex (MHC) class I molecules. 14 It has been shown that this phenomenon is dose and time dependent and takes place after saturation of all HER2/neu cellular receptors by trastuzumab. 15 Trastuzumab-pretreated cancer cells show a significantly enhanced cell lysis when incubated with HER2/neu-derived peptides E75 and GP2–specific CD8+ T lymphocytes, thus confirming the increased epitope presentation of HER2/neu peptides on MHC class I. 15 In a recent clinical trial on tumor vaccination, it was observed that women who had completed therapy with trastuzumab had a significant superior E75-specific CD8+ T cell response to the first vaccination with E75 peptide. 16 This demonstrates that the immunological effect of trastuzumab persists even after the antibody has been cleared and most importantly, that trastuzumab is able to induce a long lasting immunological effect, thereby indicating the generation of a memory immune response. Trastuzumab is also able to reduce circulating regulatory T cells (Tregs) 17 and alter the balance between Tregs and TH17. 18

Trastuzumab has changed the natural history of HER2/neu-positive breast cancer19-24 and represents the most important proof of concept justifying the introduction in the clinical practice of target therapies. Due to the …