Sex dimorphism and cancer immunotherapy: May pregnancy solve the puzzle?

In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetalantigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal -antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a reglatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetalmaternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.

Automated summary

In the era of immunoncology, there is growing evidence of a clear sex dimorphism in antitumor immune response, which could have an impact on immune checkpoint blockade (ICI) therapy in cancer patients. Pregnancy may lead to changes in the immune system, including the presence of memory T-cells with fetal antigen specificity and fetalmaternal microchimerism, which could have implications for cancer development and response to immunotherapy.