We have previously shown that tumor cell death with expression of hsp70, is potently immunogenic. However, since many melanoma antigens are also normal melanocyte differentiation antigens, anti-melanoma immunity is often accompanied by autoimmunity. In order to exploit this, we hypothesized that pro-inflammatory killing of normal cells would, under certain conditions, break tolerance to normal self antigens of that tissue and that these autoimmune responses would also target shared antigens on associated tumors. We showed that hsp- mediated killing of normal melanocytes primes self-reactive T cells able to clear metastatic melanomas but without overt autoimmunity because the T cell response was rapidly suppressed by regulatory T cells (Treg). Inclusion of additional T cell co-stimulation (CD40L) cleared larger established tumors, possibly by controlling Treg activity. A clinical trial of this approach for Stage IV melanoma is due to commence at the Mayo Clinic in the Spring of 2008 once the plasmids have been manufactured. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic'melanocyte/melanoma paradigm. To address this, we generated two novel models of autoimmune disease in which the immunological responses, to the same pathogenic-like insult (hsp70-mediated inflammatory killing), are profoundly different. Our data show that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-?-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease by determining the cellular/molecular basis of the different responses of the prostate (Specific Aim 1) and pancreas (Specific Aim 2) to hsp70-mediated inflammatory killing. We will also develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection and whether such effectors can treat metastatic tumors (Specific Aim 3). These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer.

Public Health Relevance

We have shown that that pro-inflammatory killing of normal melanocytes can, under certain conditions, break tolerance to normal self antigens and that these autoimmune responses also target shared antigens on associated melanomas. The overall goal of this application is to define, and characterize, the immunological connectivity between autoimmune and anti-tumor responses for other normal cell types beyond the classically `highly immunogenic'melanocyte/melanoma paradigm. To address this, we have shown that the aetiology/severity of autoimmunity depends critically upon innate, organ specific cytokine responses to key initiating signals (hsp70), and can lead to very diverse adaptive T cell responses (Th17, progressive autoimmunity in the prostate, or TGF-2-dependent protective Treg, in the pancreas). These models also reveal a close mechanistic relationship between autoimmune and anti-tumor responses in these tissues. We will now build on these data to gain a better understanding of the aetiology, and treatment, of autoimmune disease, and we will develop novel approaches to tumor immunotherapy by determining whether the effector molecules/cells of autoimmunity are the same, or different from, mediators of tumor rejection. These experiments will have significance to a broad range of disciplines including autoimmunity, innate/adaptive immune signaling pathways and tumor immunology and will drive implementation of novel immunotherapy clinical trials for prostate and, possibly, pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132734-05
Application #
8260203
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2008-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$304,127
Indirect Cost
$102,852
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Rajani, Karishma; Parrish, Christopher; Kottke, Timothy et al. (2016) Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. Mol Ther 24:166-74
Zaidi, Shane; Blanchard, Miran; Shim, Kevin et al. (2015) Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. Mol Ther 23:845-56
Blanchard, Miran; Shim, Kevin G; Grams, Michael P et al. (2015) Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. Int J Radiat Oncol Biol Phys 93:577-87
Ilett, Elizabeth; Kottke, Timothy; Donnelly, Oliver et al. (2014) Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Mol Ther 22:1851-63
Alonso-Camino, Vanesa; Rajani, Karishma; Kottke, Timothy et al. (2014) The profile of tumor antigens which can be targeted by immunotherapy depends upon the tumor's anatomical site. Mol Ther 22:1936-48
Rommelfanger, Diana M; Compte, Marta; Grau, Marta C et al. (2013) The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice. Mol Ther 21:348-57
Boisgerault, Nicolas; Kottke, Timothy; Pulido, Jose et al. (2013) Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. Mol Ther 21:1507-16
Kottke, Timothy; Boisgerault, Nicolas; Diaz, Rosa Maria et al. (2013) Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat Med 19:1625-31
Rommelfanger, Diana M; Wongthida, Phonphimon; Diaz, Rosa M et al. (2012) Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer. Cancer Res 72:4753-64
Pulido, Jose; Kottke, Timothy; Thompson, Jill et al. (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol 30:337-43

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