Concomitant tumor immunity is the response whereby a host with a progressive tumor rejects an inoculum of the same tumor at a distal site. This tumor-primed, T cell-mediated protection was previously thought to occur only with highly-immunogenic tumors. However, we have recently found that concomitant immunity to poorly-immunogenic tumors can be induced by the depletion of regulatory T cells (Tregs). The proposed studies will characterize the mechanisms that govern the induction, maintenance, and suppression of concomitant immunity. This research will employ a poorly-immunogenic mouse melanoma model that closely resembles human disease. This proposal will test the hypothesis that progressive, poorly-immunogenic tumors have the capacity to instruct durable immunity to cancer.
Specific Aim 1 will identify mechanisms for the maintenance of concomitant immunity following the surgical excision of primary tumors. Studies will characterize long-term post-excisional protection against local and metastatic melanoma. Protection will be correlated with the tumor-induced priming of central and effector memory T cell responses against multiple melanoma-expressed self antigens.
Specific Aim 2 will define the mechanisms whereby optimum concomitant immunity is induced. The stimulation of various T cell populations through GITR (glucocorticoid-induced TNFR family-related protein), as well as the administration of lymphodepleting chemotherapy will be investigated as methods for driving activation and proliferation of CD8+ effector and CD4+ helper T cells in tumor-bearing hosts. By monitoring concomitant immunity, these studies will reveal the generation of protective immune responses that would otherwise remain undetected in tumor-bearing hosts.
Specific Aim 3 will define mechanisms whereby tumors suppress concomitant immunity. Studies will rely on transgenic mice expressing a Foxp3-GFP reporter gene to enable the precise characterization of Tregs in tumor-bearing mice. Results are expected to demonstrate that progressive, poorly-immunogenic melanoma induces priming and expansion of Tregs that are specific for tumor-expressed self antigens. Collectively, the proposed studies will define mechanisms for generating durable, T cell-mediated immunity in hosts bearing poorly-immunogenic tumors, without the use of active immunization (vaccines). These studies are expected to demonstrate that manipulating the host's own immune milieu during tumor growth is sufficient for inducing long-lived protection against recurrent and metastatic disease. ? ? Surgery is currently the most successful treatment for solid tumors. However, patients continue to succumb to metastatic disease. This research is expected to lead to therapies which will utilize patients' own immune systems to prevent the recurrence and metastasis of cancers following surgery. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120777-02
Application #
7253104
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$275,593
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Malik, Brian T; Byrne, Katelyn T; Vella, Jennifer L et al. (2017) Resident memory T cells in the skin mediate durable immunity to melanoma. Sci Immunol 2:
Li, Na; Xu, Wenwen; Yuan, Ying et al. (2017) Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 7:1485
Steinberg, Shannon M; Shabaneh, Tamer B; Zhang, Peisheng et al. (2017) Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors. Cancer Res 77:1599-1610
Clark, Curtis A; Gupta, Harshita B; Sareddy, Gangadhara et al. (2016) Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. Cancer Res 76:6964-6974
Whipple, Chery A; Boni, Andrea; Fisher, Jan L et al. (2016) The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. Melanoma Res 26:223-35
Steinberg, Shannon M; Turk, Mary Jo (2015) BRAF-inhibition and tumor immune suppression. Oncoimmunology 4:e988039
Clancy-Thompson, Eleanor; Perekslis, Thomas J; Croteau, Walburga et al. (2015) Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease. Cancer Immunol Res 3:956-67
Jenkins, Molly H; Steinberg, Shannon M; Alexander, Matthew P et al. (2014) Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032. Pigment Cell Melanoma Res 27:495-501
Byrne, Katelyn T; Zhang, Peisheng; Steinberg, Shannon M et al. (2014) Autoimmune vitiligo does not require the ongoing priming of naive CD8 T cells for disease progression or associated protection against melanoma. J Immunol 192:1433-9
Steinberg, Shannon M; Zhang, Peisheng; Malik, Brian T et al. (2014) BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. Cancer Immunol Res 2:1044-50

Showing the most recent 10 out of 20 publications