CONTRIBUTIONS TO SCIENCE & MEDICINE
Our research has focused on understanding T cell tolerance and mechanisms that control the decision between T cell tolerance versus activation. We are particularly focused on how to activate ignorant tissue specific T cells to promote anti-tumor immunity and improve immunotherapy. We have investigated T cell signaling pathways that promotes activation as well as the role of the antigen presenting cell (APC) and signals controlling APC maturation.
A. T cell ignorance occurs to sequestered tissue specific self antigens. We showed that tissue specific cells persist in the T cell repertoire and could be activated by pathogens carrying the model self antigen. This led to the CD8 mediated destruction of tissues bearing the model antigen. Further studies demonstrated that tumor development resulted in the same model antigen being detected by the immune system and initiating an immune response. Therefore T cell ignorance was converted to activation by tumor growth; illustrating the concept of immune surveillance. Using this model we have shown that immune surveillance is dependent upon TNFα. Because we demonstrated that immune surveillance activated tissue/tumor specific T cells, we went on to establish TIL therapy in at our institute.
- Ohashi, P.S., Oehen, S., Bürki, K., Pircher, H., Ohashi, C.T., Odermatt, B., Malissen, B., Zinkernagel, R.M., and Hengartner, H. (1991) Ablation of "tolerance" and induction of diabetes in viral antigen transgenic mice. Cell 65:305-317.
- Nguyen, L.T., Elford, A.R., Murakami, K., Garza, K.M., Schoenberger, S.P., Odermatt, B., Speiser, D. and Ohashi, P.S. (2002) Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance. J. Exp. Med. 195:423-435.
- Calzascia, T., Pellegrini, M., Hall, H., Sabbagh, L., Ono, N., Elford, A.R., Ohashi, P.S. (2007) TNF-alpha is critical for anti-tumor but not anti-viral T cell immunity. J. Clin. Invest. 117:3833-3845. ** highlighted in Nature Immunology Reviews, December issue.
- Nguyen, L.T., Yen, P.H., Nie, J., Liadis, N., Ghazarian, D., Al-Habeeb, A., Easson, A., Leong, W., Lipa, J., McCready, D., Reedijk, M., Hogg, D., Joshua, A.M., Quirt, I., Messner, H., Shaw, P., Crump, M., Sharon, E. and Ohashi, P.S. (2010) Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs). PLoS ONE 5(11):e13940.
B. APCs must be matured through signals such as anti-CD40 or LPS in order to promote T cell activation instead of tolerance. To understand how tumor specific T cells are activated in vivo, we searched for potential endogenous signals that could promote APC maturation. Our work showed that APC maturation is also mediated by heat shock proteins. Recently we have also uncovered an unexpected finding in DC biology. We have shown that the immature dendritic cell is programmed to exist in a quiescent state. Removing key signaling molecules, alter DC quiescence and lead to an altered DC state that is sufficient to activate CD8+ T cells in vivo. It is important to understand whether this process is associated with immune surveillance in patients.
- Garza, K.M., Chan, S.M., Suri, R., Nguyen, L.T., Odermatt, B., Schoenberger, S.P. and Ohashi, P.S. (2000) Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 191:2021-2027.
- Millar, D.G., Garza, K.M., Odermatt, B., Elford, A.R., Ono, N., Li, Z. and Ohashi, P.S. (2003) Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat. Med. 9:1469-1476.
- Dissanayake, D., Hall, H., Berg-Brown, N., Elford, A.R., Hamilton, S.R., Murakami, K., Summers Deluca, L., Gommerman, J.L. and Ohashi, P.S. (2011) NF-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T-cells. Nat Med. 17(12):1663-1667 *highlighted in Nat Med. News and Views p1554-1556.
C. Examining key molecules associated with T cell activation or tolerance. Because APCs maturation is a key process that determines whether T cells are tolerized or activated upon encountering antigen, we also examined key molecules that are involved in this process. We evaluated the importance of CD28 signals, and downstream signaling pathways. More recently we have examined the role of inhibitory molecule B7-H4 and surprisingly identified a positive role for this family member in anti-tumor immunity.
- Kündig, T.M., Shahinian A., Kawai, K., Mittrücker, H-W., Sebzda, E., Bachmann, M.F., Mak, T.W. and Ohashi, P.S. (1996) Duration of TCR stimulation determines costimulatory requirement of T cells. Immunity 5:41-52.
- Jones, R.G., Elford, A.R., Parsons, M.J., Wu, L., Krawczyk, C.M., Yeh, W.-C., Hakem, R., Rottapel, R., Woodgett, J.R. and Ohashi, P.S. (2002) CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J. Exp. Med. 196:335-348. ** highlighted in Nature Immunology Reviews
- Berg-Brown, N.N., Gronski, M.A., Jones, R.G., Elford, A.R., Deenick, E.K., Odermatt, B., Littman, D.R. and Ohashi, P.S. (2004) PKCq signals activation versus tolerance in vivo. J. Exp. Med. 199:743-752.
- Rahbar, R., Lin, A., Ghazarian, M., Loo Yau, H., Paramathas, S., Lang, P., Schildknecht, A., Elford, A.R., Garcia-Batres, C., Martin, B., Berman, H., Leong, W.L., McCready, D.R., Reedijk, M., Done, SJ., Miller, N., Youngson, B., Suh, W-K, Mak, T.W., Ohashi, P.S. (2015) B7-H4 Expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity. Cancer Immunology Research. 3: 184-195.
D. Novel role of IL-7 in enhancing tumor vaccines. Our models were used to study the efficacy of tumor vaccines. Unlike transplantable tumor models, our model demonstrated that tumor vaccines were unable to control tumor growth. We also evaluated strategies to improve anti-tumor immunity and demonstrated that IL-7 was able to act via several mechanisms to improve T cell function.
- Speiser, D.E., Miranda, R., Zakarian, A., Bachmann, M.F., McKall-Faienza, K., Odermatt, B., Hanahan, D., Zinkernagel, R.M., and Ohashi, P.S. (1997) Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J. Exp. Med. 186:645-653.
- Pellegrini, M., Calzascia, T., Elford, A.R., Shahinian, A., Lin, A.E., Dissanayake, D., Dhanji, S., Nguyen, L.T., Gronski, M.A., Morre, M., Assouline, B., Lahl, K., Sparwasser, T., Ohashi, P.S.* and Mak, T.W. (2009) Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med. 15:528-36. *shared senior author, corresponding author
- Pellegrini, M., Calzascia, T., Toe, J.G., Preston, S.P., Lin, A.E., Elford, A.R., Shahinian, A., Lang, P.A., Lang, K.S., Morre, M., Assouline, B., Lahl, K., Sparwasser, T., Tedder, T.F., Paik, J., DePinho, R. A., Basta, S., Ohashi, P.S. and Mak, T. (2011) IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144(4):601-13. *shared senior author, corresponding author; **highlighted by the Faculty of 1000, InCITE and Nature Reviews Immunology
E. Immunoscore Collaboration Project. As our interest in immunotherapy has grown, so have our connections at the global level. We have participated in initiatives related to immune therapy as outlined in the publications below. We are currently involved in developing ‘Immunoscore’ for colon cancer in a world-wide initiative, and are the representative Canadian site.
- Fox, B.A., Schendel, D., Butterfield, L.H., Allison, J., Ascierto, P.A., Atkins, M.A, Bartunkova, J., Bergmann, L., Bramson, J., Britten, C. M., Carson W.E., Characiejus, D., Choudhury, R., Coukos, G., Finke, J., Gollob,J.A., Gouttefangeas, C., Grizzi, F., Guida, M., Haakanson, L., Hege, K., Hodi, F. S., Hoos, A., Hwu, P., Kaufman, H., Kawakami, K., Kawakami, Y., Khleif, S., Kiessling, R., Y., Jaffee, E.M., Janetski, S., June, C.H., Lapointe, R., Levitsky, H., Maio, M., Murphy, W., Maccalli, C., Masucci, G., Nelson, B., Nicolini, A., Ohashi, P.S., Ottensmeier, C., Papamichail, M., Parmiani, G., Pawelec, G., Proietti, E., Qin, S., Ribas, A., Rivoltini, L., Romero, P., Sharma, P., Seliger, B., Shiku, H., Song, W.R., Stratten, P.T., Tahara, H., van der Burg, S. H., von Hoegen, P., Wang, E., Welters, M., Wolchok, J., Zweirzina, H., L. Marincola, F., Gajewski, T., Wigginton, J., Disis, M.L. (2011) Defining the Critical Hurdles in Cancer Immunotherapy. J. Trans. Med. 2011, 9:214 doi: 10.1188/1479-5876-9-214
- Galon, J., Pages, F., Marincola, F., Thurin, M., Lugli, A., Zlobec, I., Bifulco, C., Botti, G., Tatangelo, F., Britten, C., Chouchane, L., DelRio, P., Hartmann, A., Asslaber, M., Maio, M., Masucci, G.V., Mihm, M., Angell, H., Vidal-Vanaclocha, F., Allison, J., Gnjatic, S., Hakansson, L., Huber, C., Singh, H., Ottensmeier, C., Zwierzina, H., Laghi, L., Grizzi, F., Ohashi, P.S., Shaw, P.A., Clarke, B., Wouters, B., Wang, E., O’Donnell-Tormey, J., Maio, M., Lagorce, C., Pawelec, G., Nishimura, M.I., Hawkins, R., Lapointe, R., Kreiter, S., Lundqvist, A., Khleif, S.N., Ogino, S., Gibbs, P., Waring, P., Sato, N., Torigoe, T., Itoh, K., Palmqvist, R., Nagtegaal, I.D., Wang, Y., D’Arrigo, C., Kopetz, S., Sinicrope, F., Trinchieri G., Gajewski, R.F., Ascierto, P.A., Fox, B.A. (2012) Cancer classification using the Immunoscore: A worldwide task force. J. Transl. Med. 10(1):205
- Pagès, F. Mlecnik, B. Marliot, F. Bindea, G. Ou, FS. Bifulco, C. ... Ohashi, PS. Nguyen, LT. Han, S. MacGregor, H. ... Galon, J. (2018). International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. The Lancet 391(10135):2128-2139.
F. Understanding CD8+ T cell regulation for improving immunotherapy. To improve immunotherapy, it is critical to understand how CD8+ T cell function is regulated. We have uncovered a previously unappreciated role for Innate lymphoid cells to regulate anti-viral immunity and anti-tumor immunity.
- Lang, P.A., Lang, K.S., Xu, H.C., Grusdat, M., Parish, I.A., Recher, M., Elford, A.R., Dhanji, S., Shaabani, N., Tran C.W., Dissanayake, D., Rahbar, R., Ghazarian, M., Brustle, A., Fine, J., Chen, P., Weaver, C.T., Klose, C., Diefenbach, A., Haussinger, D., Carlyle, J.R., Kaech, S.M., Mak, T.W., Ohashi, P.S. (2012) Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. PNAS 109(4):1210-15 *highlighted in Commentary section of PNAS Early Edition doi:10.1073/pnas.1120528109 Yet another role for natural killer cells: Biron, CA.
- Crome, S.Q., Nguyen, L.T., Lopez-Verges, S., Yang, SYC., Martin, B., Yam, J.Y., Johnson, D.J., Nie, J., Pniak, M., Yen, P.H., Milea, A., Sowamber, R., Katz, S.R., Bernardini, M.Q., Clarke, B.A., Shaw, P.A., Lang, P.A., Berman, H.K., Pugh, T.J., Lanier, L.L., and Ohashi, P.S. (2017) A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med. 23(3);368-378 **highlighted in Cancer Discovery doi:10.1158/2159-8290.