Abstract

Self-antigens, in the form of differentiation antigens, are commonly recognized on melanoma and other cancers by the immune system. It has been unclear whether recognition of these antigens is relevant to immunity to cancer. The tyrosinase family has emerged as prototypes of differentiation antigens on human cancers. We actually do not know very much about immune recognition of these antigens, or other differentiation antigens. Recognition of these antigens presents many problems. First, how is recognition of these antigens possible in the face of immune tolerance. Second, even when recognition is possible, can this generate immunity that can reject cancer. Finally, if immunity to differentiation antigens can reject cancer, what are the potential autoimmune sequelae. We have used a mouse melanoma model to show that mice can be tolerant to tyrosinase family antigens. Tolerance can be broken by immunization wit altered forms of antigen. This can generate antibody and CD8+ T cell responses that are capable of rejecting tumors. CD4+ cells are required for immunity.
Our aims are to: 1) Investigate how cancer immunity is uncoupled from autoimmunity; 2) Investigate the role of CD4+ T cell responses in tumor immunity against differentiation antigens.; and 3) Develop mouse models that develop endogenous invasive melanomas and study immunity against differentiation antigens at different steps in tumor progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056821-08
Application #
6328926
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Hecht, Toby T
Project Start
1992-06-01
Project End
2004-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
8
Fiscal Year
2001
Total Cost
$240,172
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Ribas, Antoni; Wolchok, Jedd D (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350-1355
Ricca, Jacob M; Oseledchyk, Anton; Walther, Tyler et al. (2018) Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy. Mol Ther 26:1008-1019
Oseledchyk, Anton; Ricca, Jacob M; Gigoux, Mathieu et al. (2018) Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus. Oncotarget 9:28702-28716
Zamarin, Dmitriy; Ricca, Jacob M; Sadekova, Svetlana et al. (2018) PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Invest 128:1413-1428
Zamarin, Dmitriy; Holmgaard, Rikke B; Ricca, Jacob et al. (2017) Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat Commun 8:14340
Dai, Peihong; Wang, Weiyi; Yang, Ning et al. (2017) Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci Immunol 2:
Budhu, Sadna; Schaer, David A; Li, Yongbiao et al. (2017) Blockade of surface-bound TGF-? on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal 10:
Malandro, Nicole; Budhu, Sadna; Kuhn, Nicholas F et al. (2016) Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion. Immunity 44:179-193
Holmgaard, Rikke B; Brachfeld, Alexandra; Gasmi, Billel et al. (2016) Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy. Oncoimmunology 5:e1151595
Holmgaard, Rikke B; Zamarin, Dmitriy; Lesokhin, Alexander et al. (2016) Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine 6:50-58

Showing the most recent 10 out of 78 publications