title: RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors.
abstract: OBJECTIVE
  Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.
  
  
  METHODS
  We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer.
  
  
  RESULTS
  Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.
  
  
  CONCLUSIONS
  These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia. justin.balko@vanderbilt.edu sherene.loi@petermac.org.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Sathana
authors.initials: S
authors.lastname: Dushyanthen
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.affiliation: Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels, Department of Pathology, GZA Antwerp, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Charité University and German Cancer Consortium (DKTK), Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Savas
authors.affiliation: Departments of Pathology and Medicine, Yale University, New Haven, Connecticut.
authors.forename: Susan
authors.initials: S
authors.lastname: Combs
authors.affiliation: Departments of Pathology and Medicine, Yale University, New Haven, Connecticut.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Giltnane
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pilkinton
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Phil J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú.
authors.forename: Franco D
authors.initials: FD
authors.lastname: Doimi
authors.affiliation: Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú.
authors.forename: Henry
authors.initials: H
authors.lastname: Gómez
authors.affiliation: Maine Medical Center Research Institute, Scarborough, Maine.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ryzhov
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee. justin.balko@vanderbilt.edu sherene.loi@petermac.org.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009026:Mortality; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; D015415:Biomarkers; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins