Abstract
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.
Highlights
Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
In tumor microenvironment (TME), while IFN type I (IFN-I) signaling is critical for survival and full activation of CD8+ T cells, the continuous generation of terminally differentiated CD8+ T cells might determine the failure of immune checkpoint blockade (ICB) by reducing progenitors able to respond [30]
This central achievement occurs through the modulation of different transcriptional programs involving the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and IFN regulatory factors (IRFs) families, as well as proteins of the phosphatidyl inositide3-kinase (PI3K) and mitogen-activated protein kinases (MAPK) pathways [44]
Summary
In the era of ICIs, T-cell immunity remains central for tumor regression [8]. This is far from being simple and occurs only when diverse elements coexist either during cancer immunosurveillance or immunotherapeutic treatments [9]. Treg-mediated immune tolerance may occur through the control of IFN-I on indoleamine 2,3-dioxygenase (IDO) [38, 39], being melanoma peritumoral IDO expression by pDCs an early marker of resistance [40] Both Tregs and IFN-I suppress the function of natural killer (NK) cells whose antigen-independent cytotoxicity is the second effector mechanism responsible for an efficacious antitumor response [41, 42]. These immune components build a functional framework for innate and acquired resistance to PD-1 blockade [43], where the balance between inflammation and suppression determined by the fine-tune regulation of IFN-I is crucial This central achievement occurs through the modulation of different transcriptional programs involving the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and IFN regulatory factors (IRFs) families, as well as proteins of the phosphatidyl inositide3-kinase (PI3K) and mitogen-activated protein kinases (MAPK) pathways [44]. Immune-related adverse events (irAEs), such as the loss of the protective function of intestinal barriers and changes occurring in the microbiota composition, represent the most frequent ICI-associated toxicities to which dysregulated activation of the IFN-I signaling may contribute [49, 50]
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