OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor.
Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-beta. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor.
Gough
Michael J
MJ
Robert W Franz Cancer Center, Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon 97213, USA.
Ruby
Carl E
CE
Redmond
William L
WL
Dhungel
Birat
B
Brown
Alexis
A
Weinberg
Andrew D
AD
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016827:CD8 Antigens / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D007108:Immune Tolerance / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy*; D053278:OX40 Ligand; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000187:drug effects* / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000819:agonists* / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016827:CD8 Antigens; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors