title: Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium.
abstract: OBJECTIVE
  Male-based studies, both at the biochemical and at the pre-clinical/clinical trial levels, still predominate in the scientific community. Many studies are based on the wrong assumption that both sexes are fundamentally identical in their response to treatments. As a result, findings obtained mainly in males are applied to females, resulting in negative consequences female patients. In cancer immunotherapy, there is still a scarce focus on this topic. Here we review the main differences in immune modulation and immune system biology between males and females with a particular focus on how these differences affect cancer immunotherapy and cancer vaccines.
  
  
  METHODS
  We reviewed articles published on PubMed from 1999 to 2014, using the keywords: sex hormones, immune response, estrogen, immunotherapy, testosterone, cancer vaccines, sex-based medicine. We also present new data wherein the expression of the cancer testis antigen, Ropporin-1, was determined in patients with multiple myeloma, showing that the expression of Ropporin-1 was influenced by sex.
  
  
  RESULTS
  Male and female immune systems display radical differences mainly due to the immune regulatory effects of sex hormones. These differences might have a dramatic impact on the immunological treatment of cancer. Moreover, the expression of tumor antigens that can be targeted by anti-cancer vaccines is associated with sex.
  
  
  CONCLUSIONS
  Future clinical trials focusing on cancer immunotherapy will need to take into account the differences in the immune response and in the frequency of target antigen expression between male and females, in order to optimize these anti-cancer immunotherapies of the third millennium.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center , Lubbock, TX , USA.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mirandola
authors.forename: Raymond
authors.initials: R
authors.lastname: Wade
authors.forename: Rashmi
authors.initials: R
authors.lastname: Verma
authors.forename: Camilo
authors.initials: C
authors.lastname: Pena
authors.forename: Nattamol
authors.initials: N
authors.lastname: Hosiriluck
authors.forename: Jose A
authors.initials: JA
authors.lastname: Figueroa
authors.forename: Everardo
authors.initials: E
authors.lastname: Cobos
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Jenkins
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiriva-Internati
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D019496:Cancer Vaccines; D002986:Clinical Trials as Topic; D005260:Female; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000276:immunology*; D006801:Humans; D007109:Immunity; D007167:Immunotherapy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012723:Sex; D012737:Sex Factors; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D012739:Gonadal Steroid Hormones; D008565:Membrane Proteins; C404565:ROPN1 protein, human; D020741:rho GTP-Binding Proteins
keywords: cancer vaccines; cancer/testis atigens; hormones; immune response