Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer.
Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.
Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637 ; Department of Pathology, The University of Chicago, Chicago, IL 60637.
David C
DC
Binder
Department of Pathology, The University of Chicago, Chicago, IL 60637 ; Committee on Immunology, The University of Chicago, Chicago, IL 60637.
Boris
B
Engels
Department of Pathology, The University of Chicago, Chicago, IL 60637 ; Committee on Immunology, The University of Chicago, Chicago, IL 60637.
Ainhoa
A
Arina
Committee on Immunology, The University of Chicago, Chicago, IL 60637 ; Department of Medicine, The University of Chicago, Chicago, IL 60637.
Ping
P
Yu
Department of Microbiology and College of Medicine, University of Illinois, Urbana, IL 61801.
James M
JM
Slauch
Department of Pathology, The University of Chicago, Chicago, IL 60637 ; Committee on Immunology, The University of Chicago, Chicago, IL 60637.
Yang-Xin
YX
Fu
Department of Health Sciences, The University of Chicago, Chicago, IL 60637.
Theodore
T
Karrison
Department of Radiation Oncology, The University of Chicago, Chicago, IL 60637.
Byron
B
Burnette
Department of Pathology, The University of Chicago, Chicago, IL 60637 ; Committee on Immunology, The University of Chicago, Chicago, IL 60637 ; Department of Otorhinolaryngology, University of Lübeck, Lübeck, Germany.
Christian
C
Idel
AntiCancer, Inc., San Diego, CA 92111.
Ming
M
Zhao
AntiCancer, Inc., San Diego, CA 92111 ; Dept. of Surgery, University of California San Diego, San Diego, CA 92103-8220.
Robert M
RM
Hoffman
Georgia Health Sciences University Cancer Center, Augusta, GA 30912.
David H
DH
Munn
Department of Pathology, The University of Chicago, Chicago, IL 60637.
Donald A
DA
Rowley
Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637 ; Department of Pathology, The University of Chicago, Chicago, IL 60637 ; Committee on Immunology, The University of Chicago, Chicago, IL 60637.
Hans
H
Schreiber
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000939:Epitopes; D005260:Female; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D000939:Epitopes; C110366:OVA-8; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D010047:Ovalbumin
CD8+ T cell rescue; PD-L1; S. Typhimurium; Tumor rejection; vaccine