Concha LB, Carlson HE, Heimann A, et al. exact tumor and tissues antigen(s) involved in the tumor response and toxicity are unknown. It is still unclear whether the effects are a result of T cells specifically acting against antigens shared by tumor and normal cells or a result of concomitant activation of multiple populations with separate antihost and Peptide M antitumor activities [8, 19, 20, 66]. Melan-A, an antigen Tap1 shared by melanoma cells and normal melanocytes, has been associated both with tumor regression and with immune-related skin reactions [66]. In a patient affected by mM and treated with ipilimumab, marked melan-ACspecific T-cell reactivity in tumor and skin tissue was found, with CD8+ T cells localized to nevi and a simultaneous increase in melan-ACspecific CD8+ T cells in the peripheral blood [66]. It has been hypothesized that antiCCTLA-4CIH may be induced by antibodies directed against the pituitary gland [53], but the presence of antipituitary antibodies in patients who receive antiCCTLA-4 mAbs remains to be demonstrated. To the best of our knowledge, the diagnosis of antiCCTLA-4CIH has always been made Peptide M by clinical, laboratory, and radiological data. No patient has undergone a pituitary biopsy. Indeed, biopsy of the pituitary gland in cancer patients suspected of having developed antiCCTLA-4CIH raises a series of ethical issues, and it is not necessary either for diagnosis or for treatment. Nonetheless, this remains the only way to obtain essential information to improve our knowledge on the pathophysiology of this IRAE. Pituitary autoimmunity is a complex and incompletely defined spectrum of clinical conditions [26], ranging from histologically proven forms of LYH/AH to the presence of pituitary antibodies in apparently healthy individuals [28]. Interestingly, Mirocha et al. [67] observed two distinct entities of primary LYH that can be distinguished on the basis of the prevalence of T-regs or T-17 helper lymphocytes (THL-17). One of these entities, in agreement with the classical description of LYH/AIH, demonstrates an autoimmune process with THL-17 dominance and lack of T-regs. The other one appears as a process in which T-regs control the immune response, which may not be self-targeted but foreign targeted (infective agents?). Hypophysitis triggered by an immune homeostatic process should not be treated with immunosuppression, whereas autoimmune-sustained hypophysitis may benefit from it [67]. Patients with antiCCTLA-4CIH usually benefit from corticosteroids and this ex juvantibus criterion, together with other clinical aspects, may indirectly confirm its autoimmune pathogenesis. The potential of the precautionary use of steroids in reducing the long-term sequelae of this E-IRAE, especially in preventing prolonged substitutive treatment, still remains to be evaluated. Because the hurdles in defining the histological Peptide M characteristics of antiCCTLA-4CIH persist, antiCCTLA-4CIH offers a unique opportunity to assess the fluctuation of the available pituitary antigens and relative antibodies, with the aim to improve their reliability as diagnostic and predictive tools. Pituitary antigens and antibodies could be monitored in a homogeneous cohort of patients with a specific disease and known pituitary-damaging agents, such as antiCCTLA-4 mAbs, at baseline, before each cycle of treatment, and during follow-up. Such a study would offer the possibility of defining a series of important clinical, laboratory, and radiological correlations, including refinement of the diagnosis and the real incidence of antiCCTLA-4CIH, the potential existence of a subclinical form of antiCCTLA-4CIH, the impact (if any) of this syndrome on the quality of life of patients, and the possible predisposition of a subgroup of these patients to develop antiCCTLA-4CIH and other E-AEs. This approach appears even more logical in light of recent data regarding the predictive role of antibodies to thyroglobulin and thyroperoxidase and Peptide M the TSH receptor in the development of thyroid autoimmune disease [68]. Similarly, in a population of patients with autoimmune.
