title: Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery.
abstract: Each year, more than 700,000 people undergo cancer surgery in the United States. However, more than 40% of those patients develop recurrences and have a poor outcome. Traditionally, the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy. However, we found that tumor cells have few phenotypical differences after surgery. Thus, we propose an alternative explanation for the resistance of recurrent tumors. Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly. Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b(+)F4/80(hi)CD206(hi) and CD11b(+)F4/80(hi)CD124(hi)) macrophages and CD4(+)Foxp3(+) regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells. Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year.
authors.affiliation: Thoracic Surgery Research Laboratory, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jarrod
authors.initials: J
authors.lastname: Predina
authors.forename: Evgeniy
authors.initials: E
authors.lastname: Eruslanov
authors.forename: Brendan
authors.initials: B
authors.lastname: Judy
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Moon
authors.forename: Zvi Gregorio
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: Steven
authors.initials: S
authors.lastname: Albelda
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D017211:Treatment Failure; D059016:Tumor Microenvironment / Q000276:immunology*; D014611:Vaccination / Q000379:methods
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C036763:monocyte-macrophage differentiation antigen