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A short-term 4-week treatment with SSRIs enhanced NK cell cytotoxicity but not NK cell numbers,49,50 whereas long-term treatment led to increased NK cell counts.51 However, no evidence for direct effects of SSRIs on NK cells was found. However, knowledge about the expression of 5-HTRs on NK cells is very limited. This interesting link between IL-12, which is produced during infections, and GCs in NK cells, will need to be investigated further (Fig. 3).
More importantly, they demonstrated that it is of great importance to separate each cancer entity instead of pooling them together, as this could be one of the biggest barriers in properly analyzing the influence of sex in ICB therapy response (158). Regarding anti-PD-1/PD-L1 therapy male patients with colorectal cancer or glioblastoma multiforme showed increased survival, while female patients with esophagogastric cancer (ESCA) or NSCLC tended to have better OS. This analysis revealed a higher reduction in the risk of death in males compared to females upon treatment with the different ICIs. As described in the first section of this review, it is known that sex is a variable affecting both innate and adaptive immune responses (1). Moreover, only a relatively small part of cancer patients experience long-term benefit from ICI treatment and a significant number of patients experiences immune-related adverse events during therapy. In a study published by Pu et al., it was observed that orchidectomy in combination with CpG vaccine was beneficial in terms of survival and immune response in a murine model of prostate cancer. This improved efficacy was due to immune modulations preventing Treg accumulation and augmentation of effector cells infiltrating the prostate epithelium (142).
The fact, that female B cells are more efficiently positioned within GCs can result in a stronger humoral immune response and also enhance the prevalence to autoimmune diseases displayed in females. It is well-described, that regardless of age, females display in general higher numbers of B cells and basal immunoglobulin levels, resulting in greater antibody responses than males. It was also observed that the production of interleukin 2 (IL-2) was higher in stimulated spleen cells from female mice compared to male or female cells treated with testosterone. AR/androgens can influence different immune cell subsets, including T cells, B cells, macrophages, neutrophils, and dendritic cells (Left part of the figure). They participate in the immune response against cancers due to their ability to recognize molecular characteristics of stressed tumor cells, such as missing self or inducing self-recognition .
Despite the heterogeneity of cancer types and drugs used, the data suggest a beneficial effect of adrenergic receptor blockade on NK cell activity and tumor control (reviewed in ref. 77). In CD16+ lymphocytes, the expression of α1- and α2-AR was also detected.75,76 The functional effects of epinephrine were mainly attributed to β2-AR (reviewed in refs. 77,78); however, epinephrine, but not norepinephrine, was also shown to modulate the expression levels of α1- and α2-AR on NK cells in vivo.75 A recent publication supports the possible clinical relevance of dopaminergic modulation, as the treatment of patients with solid refractory tumors with a small-molecule D2 antagonist in a phase II study led to enhanced NK cell tumor infiltration and induction of cytokines.68 Based on these promising results, new studies with specific DR agonists and antagonists are required to better understand how to modulate the dopaminergic pathway in NK cells to achieve therapeutic relevance.
Recognition of infection by NK cells is accomplished by the activation of receptors on the NK cell surface, which initiate NK cell effector functions. Klein, S., Flanagan, K. Sex differences in immune responses. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Sex differences in immune responses to viruses, bacteria and vaccines.

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