The impact of sex and gender on immunotherapy outcomes

Abstract

Immunotherapies are often used for the treatment, remission, and possible cure of autoimmune diseases, infectious diseases, and cancers. Empirical evidence illustrates that females and males differ in outcomes following the use of biologics for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA), infectious diseases, e.g., influenza, and solid tumor cancers. Females tend to experience more adverse reactions than males following the use of a class of biologics referred to as immunotherapies. For immunotherapies aimed at stimulating an immune response, e.g., influenza vaccines, females develop greater responses and may experience greater efficacy than males. In contrast, for immunotherapies that repress an immune response, e.g., tumor necrosis factor (TNF) inhibitors for RA or checkpoint inhibitors for melanoma, the efficacy is reportedly greater for males than females. Despite these differences, discrepancies in reporting differences between females and males exist, with females have been historically excluded from biomedical and clinical studies. There is a critical need for research that addresses the biological (i.e., sex) as well as sociocultural (i.e., gender) causes of male-female disparities in immunotherapy responses, toxicities, and outcomes. One-size-fits-all approaches to immunotherapies will not work, and sex/gender may contribute to variable treatment success, including adherence, in clinical settings.

Keywords: Autoimmunity; CTLA-4; Cancer; Checkpoint therapy; Influenza vaccine; PD-1/PD-L1; Rheumatoid arthritis; Tumor necrosis factor (TNF) inhibitor.

Fig. 1

Both sex- and gender-based factors contribute to differences between females/women and males/men and should be considered in biomedical research. Gender influences such things as differential inclusion of individuals in biomedical and clinical studies, engagement in behavioral risk factors, access to care and treatment, health-seeking behaviors, and acceptance of immunotherapies, such as vaccines, treatment received, adherence to therapies, response to adverse reactions, and the reporting of outcomes by both patients and health providers and respondents and researchers. Biological sex can impact the pathogenesis of the targeted diseases and immune responses to immunotherapies as well as development of adverse reactions. These outcomes will be influenced by the ways in which gender and sex intersect with other biological and social stratifiers such as age, race, disability, socioeconomic status, and other factors. Together, both sex and gender, and their intersection with other biological and social stratifiers, contribute to differential efficacy of immunotherapies

Fig. 2

Hypothesized sex- and gender-based factors contributing to differences between females/women and males/men in the efficacy of immunotherapies. Based on the available data, we hypothesize that immunotherapies that stimulate the immune responses are more efficacious in females/women, whereas treatments that repress immune responses are more efficacious in males/men. Biologically, females generally have greater immune responses than males. We hypothesize that sex differences in immune function are caused by sex chromosomal (genetic) and sex steroidal (hormonal) differences between the sexes that differentially affect immune responses to immunotherapies. Sociocultural factors, including health-seeking behaviors, access to healthcare, and reporting of adverse events, also contribute to differences between women and men in immunotherapy adherence and reporting of adverse events. Together, both sex and gender contribute to differential efficacy of immunotherapies