Phone: (303) 398-1887
Many factors limit the adaptive immune system from killing tumors; tumors and the resident inflammatory cells have numerous ways of inhibiting productive B and T cell responses. In addition, most antigens on tumors are “self antigens” not “neoantigens” or mutated proteins that lead to tumor development. Therefore immune cells bind weakly to tumors and respond weakly. Poor responses to tumor/self antigens seem detrimental, but actually this protects us from other autoimmune issues. If the immune system could be better stimulated when encountering tumors, they might mediate more effective responses against the tumor. Our goal is to make this happen.
Using an animal model for colon cancer, we are determining what substitutions in tumor antigen peptides improve antitumor immunity. These so-called “mimotope” peptides (mimics of epitopes) activate T cells that respond to the tumor more effectively than the natural tumor antigen. To understand how mimotope peptides affect T cell responses against tumors, we are characterizing the T cells responding to these peptides. Using high throughput sequencing techniques, we now know that T cells that are elicited by effective vaccines have TCRs with similar sequences as those found in the tumor without a vaccine. In this system, we have also started studying the epigenome of tumor-specific T cells that respond to effective vaccines and to the tumor.
We have a collaborative DoD-supported project with the labs of Drs. John Kappler, Peter Lee (City of Hope), and Paul Spellman (OHSU). This multi-team project combines genomics and immunotherapy to develop a new generation of therapeutic breast cancer vaccines, which improve the immune system’s ability to fight breast cancer. We are working on identifying the cognate antigens and mimotopes of breast cancer infiltrating T cells by using the T cells directly out of the tumors.
Finally, two blossoming projects in the lab: 1. We are collaborating with the Director of the Lung Cancer Center at National Jewish Health, Dr. Jeff Kern and a number of thoracic surgeons on the immune cells in human lung cancer. We are dissecting the function and the targets of B cells in the tumor verses tumor-adjacent lung tissue. Like the DoD project above, we hope to identify antigens that, if included in therapeutic vaccines, would eventually improve the survival of lung cancer patients. 2. Using animal and human models for bladder cancer, we are working with Drs. Tom Flaig, Xiaoping Yang, Shandra Wilson, and Dan Theodorescu of the UCCC to identify markers and mechanisms of non-invasive bladder cancer that fails BCG treatment.
Success of these studies may have direct implications for the design and development of tumor vaccines.
Jonathan Buhrman (Immunology Graduate Program)
Katherine Waugh (Immunology Graduate Program)
Tullia Bruno (Postdoctoral Fellow)
Daniel Munson (Postdoctoral Fellow)
Taizo Nakano (Pediatric Heme/Onc Fellow)
1. Buhrman JD, KR Jordan, L U’Ren, J Sprague, CB Kemmler, and JE Slansky. Augmenting anti-tumor T cell responses to mimotope vaccination by boosting with native tumor antigens. Cancer Res In Review (2012).
2. Buhrman JD and JE Slansky. Improving T cell responses to modified peptides in tumor vaccines. Immunol Res 2012 Aug 31. [Epub ahead of print]
3. Franks AL and JE Slansky. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases, and cancer. Anticancer Res 32:3-20 (2012).
4. Jordan KR, JD Buhrman, J Sprague, BL Moore, D Gao, JW Kappler, and JE Slansky. TCR hypervariable regions expressed by T cells that respond to effective tumor vaccines. Cancer Immunol Immunother 61:1627-38 (2012).
5. Kemmler CB, ET Clambey, RM Kedl, and JE Slansky. Elevated tumor-associated antigen expression suppresses variant peptide vaccine responses. J Immunol 187: 4431-9 (2011).
6. Jordan KR, RH McMahan, CB Kemmler, JW Kappler, and JE Slansky. Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens. PNAS 107:4652-7 (2010).
7. McWilliams* JA, RT Sullivan*, KR Jordan*, RH McMahan*, CB Kemmler*, M McDuffie, and JE Slansky. T cell tolerance to an endogenous retrovirus-encoded tumor-associated antigen increases with age. Vaccine 26:1863-73 (2008) [*equal contributors].
8. Jordan KR, RH McMahan, JZ Oh, MR Pipeling, DM Pardoll, RM Kedl, JW Kappler, and JE Slansky. Baculovirus-infected insect cells expressing peptide-MHC complexes elicit protective antitumor immunity. J Immunol 180:188-97 (2008).
9. McMahan RH, JA McWilliams, KR Jordan, SW Dow, DB Wilson, and JE Slansky. Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines. J Clin Invest 116:2543-51 (2006).
10. Crawford F, KR Jordan, B Stadinski, Y Wang, E Huseby, P Marrack, JE Slansky, and JW Kappler. Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands. Immunol Rev 210:156-70 (2006).