title: Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma.
abstract: Recurrent solid malignancies are often refractory to standard therapies. Although adoptive T cell transfer may benefit select individuals, the majority of patients succumb to their disease. To address this important clinical dilemma, we developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence. During recurrence, Foxp3(+) tumor-specific CD4(+) T cells became PD-1(+) and represented >60% of the tumor-specific CD4(+) T cells in the host. Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression. Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 Abs overcame the requirement to deplete tumor-specific Tregs. In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or Ab therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer. These data highlight the need for preclinical development of combined immunotherapy approaches specifically targeting recurrent disease.
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Goding
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Wilson
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.forename: Aparna
authors.initials: A
authors.lastname: Baxi
authors.forename: Akgul
authors.initials: A
authors.lastname: Akpinarli
authors.forename: Amy
authors.initials: A
authors.lastname: Fulton
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
authors.forename: Paul Andrew
authors.initials: PA
authors.lastname: Antony
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse
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