Sex-Biased Immunity: The Hidden Variable in Immuno-oncology

Abstract The ability of an individual’s immune system to mount a productive response against the tumor is critical for the success of immunotherapy. Clinical trials in multiple tumor types have revealed that the degree and manner in which any one person’s immune system mobilizes to eliminate tumor cells can vary widely, contributing to immunotherapeutic efficacy. Efforts to uncover biological factors contributing to response rates are a crucial area of ongoing research, given the pressing clinical need to better stratify patients based on the likelihood of response to a given therapy. Although sex differences have long been observed in the field of immunobiology, the consideration of sex as a biological variable in the immunotherapeutic treatment of patients with cancer has yet to be addressed or incorporated into patient care. Over the past decade, in part due to the National Institutes of Health–mandated changes in how sex is handled as a biological variable, research has shifted markedly in how clinical and preclinical data are reported and interpreted. These changes have brought renewed attention to the ways sex shapes antitumor immunity and responses to immunotherapy. In this review, we examine the expanding body of research demonstrating that male and female immune responses differ in their effectiveness against tumors and explore the implications of these differences for responses to immunotherapy.