title: Profound impairment of adaptive immune responses by alkylating chemotherapy.
abstract: Overall, cancer vaccines have had a record of failure as an adjuvant therapy for malignancies that are treated with alkylating chemotherapy, and the contribution of standard treatment to that failure remains unclear. Vaccines aim to harness the proliferative potential of the immune system by expanding a small number of tumor-specific lymphocytes into a large number of antitumor effectors. Clinical trials are often conducted after treatment with alkylating chemotherapy, given either as standard therapy or for immunomodulatory effect. There is mounting evidence for synergy between chemotherapy and adoptive immunotherapy or vaccination against self-Ags; however, the impact of chemotherapy on lymphocytes primed against tumor neoantigens remains poorly defined. We report that clinically relevant dosages of standard alkylating chemotherapies, such as temozolomide and cyclophosphamide, significantly inhibit the proliferative abilities of lymphocytes in mice. This proliferative impairment was long-lasting and led to quantitative and qualitative defects in B and T cell responses to neoantigen vaccines. High-affinity responder lymphocytes receiving the strongest proliferative signals from vaccines experienced the greatest DNA damage responses, skewing the response toward lower-affinity responders with inferior functional characteristics. Together, these defects lead to inferior efficacy and overall survival in murine tumor models treated by neoantigen vaccines. These results suggest that clinical protocols for cancer vaccines should be designed to avoid exposing responder lymphocytes to alkylating chemotherapy.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Litterman
authors.forename: David M
authors.initials: DM
authors.lastname: Zellmer
authors.forename: Karen L
authors.initials: KL
authors.lastname: Grinnen
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hunt
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines