Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance.
Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell-mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy.
Nguyen
Linh T
LT
Departments of Immunology and Medical Biophysics, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario M5G 2M9, Canada.
Elford
Alisha R
AR
Murakami
Kiichi
K
Garza
Kristine M
KM
Schoenberger
Stephen P
SP
Odermatt
Bernhard
B
Speiser
Daniel E
DE
Ohashi
Pamela S
PS
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000008:administration & dosage / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002455:Cell Division; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D007003:Hypoglycemia / Q000150:complications; D007108:Immune Tolerance; D007157:Immunologic Surveillance; D016233:Immunotherapy, Active; D007340:Insulinoma / Q000150:complications / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011828:Radiation Chimera; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D019013:CD40 Antigens; D018960:Hyaluronan Receptors