Sexual Dimorphism Of Immune Responses: A new perspective in cancer immunotherapy

Nowadays, several types of tumors can benefit from the new frontier of immunotherapy, due to the recent increasing knowledge of the role of the immune system in cancer control. Among the new therapeutic strategies, there is the immune checkpoint blockade (ICB), able to restore an efficacious antitumor immunity and significantly prolong the overall survival (OS) of patients with advanced tumors such as melanoma and non-small cell lung cancer (NSCLC). Despite the impressive efficacy of these agents in some patients, treatment failure and resistance are frequently observed. In this regard, the signaling governed by IFN type I (IFN-I) has emerged as pivotal in orchestrating host defense. This pathway displays different activation between sexes, thus potentially contributing to sexual dimorphic differences in the immune responses to immunotherapy. This perspective article aims to critically consider the immune signals, with particular attention to IFN-I, that may differently affect female and male antitumor responses upon immunotherapy. In the last decade the increasing knowledge of the role of the immune system in cancer control has led to the development of the immune checkpoint inhibitors (ICIs), that targeting proteins acting as negative regulators of T-cell activation, reverse the tumor-induced immune tolerance. The main actors of this scene are two key molecules called cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) (1). CTLA-4 binds B7 receptors on antigen-presenting cells (APCs), thus blocking T-cell activation. Likewise, PD-1 expressed on activated T lymphocytes, upon interaction with its ligands PD-L1 and PD-L2 on APCs or tumor cells, limits their activity delivering negative signals. PD-1 is also expressed by regulatory T cells (Tregs), enhancing their function. The clinical use of ICIs has extraordinarily increased overall survival (OS) in patients with cancer, suggesting that targeting the immune checkpoint blockade (ICB) is a privileged strategy for fighting cancer (2, 3). A crucial part of this game is played by tumor-infiltrating T cells (4) and in many cases, the effectiveness of ICIs is limited by the lack of adequate antitumor immunity in the tumor microenvironment (TME) (5). To overcome this limitation, new combination therapies are being investigated (6). In this landscape, a new perspective for improving the efficacy of immunotherapy is to take into account sexually dimorphic differences of immune responses (7).