Bachelor of Science, University of Western Australia
Bachelor of Science Honours, University of Western Australia
PhD, University of Western Australia. Mentor: Dr B Scott and Prof.B.W.S Robinson.
(key words) Immunological memory, Immunological memory is the basis for long-lasting protective immunity. An important aspect of this line of defense is the class of immune cells known as CD8T lymphocytes. These cells are crucial for both clearance of viruses and limiting the growth of virally infected cells. The CD8 T cell response to virus results in the formation of a memory population of cells, which serves as a protective barrier against future insults by the same virus. Learn more about the research of Armanda Marzo, assistant professor here
During my graduate training I became interested in the factors that regulate both the induction and maintenance of anti-tumor CD8 T cells. It was during this time I was successful in pioneering the use of T cell receptor transgenic T cells in tumor immunology systems and revealed a previously unrecognized role for CD4 T cells in providing “help” for the anti-tumor CD8 T cell responses.
a. Marzo A.L., Fitzpatrick D.R., Robinson B.W.S., and Scott B. Antisense oligonucleotides specific for transforming growth factor-beta 2 inhibit the growth of malignant mesothelioma (MM) both in vitro and in vivo. Cancer Res. 1997;57 (15): 3200-3207.
b. Marzo A.L., Lake R.A., Robinson,B.W.S., and Scott B. TCR transgenic analysis of tumor specific CD8 and CD4 responses in the eradication of solid tumors. Cancer Res. 1999;59(5): 1071-1079.
c. Marzo A.L., Lake R.A., Lo D., Sherman L., McWilliam A., Nelson D., Robinson B.W.S., and Scott, B. Tumor antigens are constitutively presented in the draining lymph nodes. J Immunol. 1999;162(10):5838-5845.
d. Marzo AL, Kinnear BF, Lake RA, Frelinger JJ, Collins EJ, Robinson BW, Scott B. Tumor-specific
CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity. J Immunol. 2000;165(11):6047-55.
2. After completing my graduate work I undertook my post-doctoral training in the laboratory of the late Leo Lefrancois at the University of Connecticut Health Center, where I broadened my research interests to include immunological T cell memory. My first significant contribution to the field of immunological memory related to the geography of CD8 T cell responses in the context of physiological infections. This body of work demonstrates that the immune response to infection can generate an army of long-lived CD8 T cells that patrol many tissues and are capable of an immediate response against re-infection.
a. Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291(5512):2413-7.
b. Masopust D, Vezys V, Marzo AL, Lefrancois L. Pillars article:Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291:2413-7. J Immunol. 2014 Feb 1: 192(3): 845-9.
c. Marzo AL,Klonowski KD, Williams KJ, Lee SJ, Pham QM, and Lefrançois L. The location of CD8 T cell activation shapes the recall response to pathogens. J. Immunol. 2006; 177(10): 6738-6746.
d. Marzo AL and Lefrançois L. Cutting Edge: The functional plasticity of memory CD8 T cells is dependent on location not phenotype. J Immunol. 2007; 179:36-40.
3. My next most important contribution to the field of immunological memory is my work published in Nature Immunology that revealed that the precursor frequency of antigen-specific CD8 T cells dictates their ability to develop into memory cells. This finding has great relevance for our ability to assess the efficacy of different immunization protocols that may be applied to developing vaccines.
a. Marzo AL, Klonowski KD, Le Bon A, Borrow P, Tough DF and Lefrancois L. Initial T cell frequency dictates memory CD8 T cell lineage commitment. Nat Immunol. 2005;6(8):793-9.
b. Lefrancois L and Marzo A.L. The descent of memory T-cell subsets. Nat Rev Immunol. 2006;6(8):618-23.
c. Marzo AL, Sowell RT, Scott B. The Role of Precursor Frequency in the Differentiation of Memory T Cells: Memory by Numbers. Memory T-cells. Adv Exp Med Biol. 2010;684:69-78. Review.
4. The next body of work relates to tumor immunology where I demonstrated a novel mechanism by which low dose irradiation enhances the efficacy of adoptively transferred tumor specific CD8 T cells. This work revealed that adoptive transfer of breast tumor specific CD8 T cells against Mammaglobin-A2 can induce tumor regression and in combination with a single low dose of irradiation prevents breast cancer relapse. The data also show that irradiation causes down regulation of the macrophage scavenger receptor 1 (Msr1) and as a consequence reduces the amount of lipid uptake by tumor resident dendritic cells allowing tumor resident dendritic cells the ability to present antigen more efficiently. Collectively, these findings point to a mechanism by which low dose TBI is acting through the down regulation of Msr1, resulting in the inhibition of lipid uptake by tumor resident DCs thus enabling these cells to present tumor antigen more efficiently to our adoptively transferred Mam-A epitope-specific CD8 T cells. This combination therapy has significant implications to the field as this regime could be used as a therapy for the treatment and/or prevention of breast cancer.
a. Nadine M. Lerret, Magdalena Rogozinska, Andrés Jaramillo and Amanda L. Marzo. Adoptive transfer of Mammaglobin-A epitope specific CD8 T cells combined with a single low dose of total body irradiation eradicates breast tumors. PLoS One. 2012;7(7):e41240. 2012 Jul 20.
b. Lerret NM, Marzo AL. Adoptive-T-cell transfer combined with a single low dose of total body irradiation eradicates breast tumors. Oncoimmunology. 2013 2(2): e22731.
5. My continued interest in CD8 T cell memory lead to my most recent publication demonstrating that the mTOR pathway is a critical regulator in determining the fate of tissue-specific CD8 T cell immunity. These data challenge the current view of how CD8 T cell responses are generated in mucosal tissues, and thus represent a fundamental advancement in elucidating the events responsible for forming protective mucosal immunity.
a. Sowell RT, Rogozinska M, Nelson CE, Vezys V, Marzo AL. Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J Immunol. 2014 Sep 1;193(5):2067-71.
b. Ryan T. Sowell and Amanda L. Marzo. Resident-memory CD8 T cells and mTOR: Generation, Protection, and Clinical Importance. Front Immunol. 2015. Feb 5:6:38.
1982 The Asthma Foundation of Western Australia Scholarship.
1995 NH&MRC Dora Lush Postgraduate Scholarship. Dec 1995 - Dec 1998
1995 Sandoz Young Investigators Award
1995 John Nott Cancer Fellowship and Research Fund.
1996 Freemasons Bursary
1996 Mary Walters Bursary. To attend the American Society of Immunology Advanced Course in
Immunology
1999 NH& MRC. C.J. Martin Fellowship (Postdoctoral Scholarship to study abroad)
2011 AAI Junior Faculty Award
2013 AAI Faculty Travel Award
2015 AAI Faculty Travel Award
2016 AAI Faculty Travel Award to attend the international Immunology conference in Australia.
Refereed journals published:
1. Marzo A.L.,Garlepp M.J., Schon-Hegrad M., and Dawkins R L. Susceptibility to murine experimental autoallergic myasthenia gravis: The role of antibody specificity.
Clin. Exp. Immunol. 1986; 64(1): 101-106 .
2. Marzo A.L., Charlton B., Stewart C., Garlepp M.J., and Dawkins R L. Influence of antibody fine specificity on development of myasthenia gravis in mice after pasive transfer of anti-ACHR.
Ann. N.Y Acad. Sci. 1987; 505: 715-717. .
3. Turner K.J., Marzo A.L., Holt B.J., Warton J.M., Papadimitriou J.M., Cameron K.J., Siemensma N.P., and Holt P G. Ultrastructural localisation of IgE in peripheral blood monocytes from atopics. Int.Archs. Allergy.Appl Immunol. 1988; 85:109-112.
4. Manning L.S., Davis M.R., Bielfeldt-Ohmann H., Marzo A.L., and Robinson B.W.S. Evaluation of immunogenicity of murine mesothelioma cells by immunization.
Europ Resp Rev. 1993; 3 (11): 234-237.
5. Fitzpatrick D.R.,Bielfeldt-Ohmann H., Himbeck R., Jarnicki A., Marzo A.L., and Robinson B.W.S. Transforming growth factor-beta: Antisense RNA-mediated inhibition affects anchorage-independent growth, tumorigenicity and T-cell infiltrating in maligant mesothelioma.
Growth Factors. 1994;11: 29-44.
6. Bielfeldt-Ohmann H.,Fitzpatrick D.R., Marzo A.L., Jarnicki A., Himbeck R., Davis M., Manning L. and Robinson, B.W.S. Patho-and immunobiology of malignant mesothelioma:characterisation of tumor infiltrating lymphocytes and cytokine production in a murine model.
Cancer Immunol. Immunother.1994;39(6):347-359.
7. Bielfeldt-Ohmann H.,Fitzpatrick D.R., Marzo A.L., Jarnicki A.., Musk A.W., and Robinson B.W.S.
Potential for interferon-alpha-based therapy in mesothelioma: assessment in the murine model. J. Interferon Cytokine Res.1995;15(3):213-223.
8. Bielfeldt-Ohmann H., Marzo A.L., Himbeck R., Jarnicki A., and Robinson B.W.S. Interleukin-6 involvement in mesothelioma pathobiology:inhibition by interferon alpha immunotherapy.
Cancer Immunol. Immunother. 1995;40(4): 241-250.
9. Marzo A.L., Fitzpatrick D.R., Robinson B.W.S., and Scott B. Antisense oligonucleotides specific for transforming growth factor-beta 2 inhibit the growth of malignant mesothelioma (MM) both in vitro and in vivo. Cancer Res. 1997;57 (15): 3200-3207.
10. Marzo A.L., Lake R.A., Robinson,B.W.S., and Scott B. TCR transgenic analysis of tumor specific CD8 and CD4 responses in the eradication of solid tumors.
Cancer Res. 1999;59(5): 1071-1079.
11. Marzo A.L., Lake R.A., Lo D., Sherman L., McWilliam A., Nelson D., Robinson B.W.S., and Scott, B. Tumor antigens are constitutively presented in the draining lymph nodes.
J Immunol. 1999;162(10):5838-5845.
12. Robinson BW, Lake RA, Nelson DJ, Scott BA, Marzo AL. Cross-presentation of tumour antigens:evaluation of threshold, duration, distribution and regulation.
Immunol Cell Biol. 1999; 77(6):552-8. Review.
13. Marzo AL, Kinnear BF, Lake RA, Frelinger JJ, Collins EJ, Robinson BW, Scott B. Tumor-specific
CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity.
J Immunol. 2000;165(11):6047-55.
14. Pope C, Kim SK, Marzo A, Masopust D, Williams K, Jiang J, Shen H, Lefrancois L. Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection.
J Immunol. 2001; 166(5):3402-9
15. Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291(5512):2413-7.
16. Robinson BW, Scott BM, Lake RA, Stumbles PA, Nelson DJ, Fisher S, Marzo AL. Lack of ignorance to tumor antigens:evaluation using nominal antigen transfection and T-cell receptor transgenic lymphocytes in Lyons-Parish analysis—implications for tumor tolerance.
Clin Cancer Res. 2001;7(3Suppl):811s-817s.
17. Marzo A.L.,Vezys V, Williams K, Tough DF, and Lefrançois L. Tissue-level regulation of Th1 and Th2 primary and memory CD4 T cells in response to Listeria infection.
J. Immunol. 2002;168(9): 4504-10.
18. Lefrancois L, Marzo AL, Masopust D, Schluns KS, Vezy V. Migration of primary and memory CD8 T cells. Adv Exp Med Biol. 2002; 512: 141-6
19. Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW. Induction of tumor cell apoptosis in vivo increases tumor antigen cross- presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol. 2003;170(10):4905-13.
20. Lefrancois L, Marzo A, and Williams K. Sustained Response Initiation Is Required for T Cell Clonal Expansion But Not for Effector or Memory Development In Vivo. J. Immunol. 2003;71: 2832-2839.
21. Masopust D, Vezys V, Usherwood EJ, Cauley LS, Olson S, Marzo AL, Ward RL, Woodland DL,
Lefrancois L. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol. 2004;172(8):4875-82.
22. Klonowski KD, Williams KJ, Marzo AL, Blair DA, Lingenheld EG, Lefrancois L.
Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity. 2004;20(5):551-62.
23. Marzo A L, Vezys V, Klonowski KD, Lee SJ, Muralimohan G, Moore M, Tough DF, and Lefrançois L. Fully functional memory CD8 T cells in the absence of CD4 T cells.
J. Immunol. 2004; 173(2):969-75.
24. Marzo AL, Klonowski KD, Le Bon A, Borrow P, Tough DF and Lefrancois L.
Initial T cell frequency dictates memory CD8 T cell lineage commitment.
Nat Immunol. 2005;6(8):793-9.
25. Lefrancois L and Marzo A.L. The descent of memory T-cell subsets.
Nat Rev Immunol. 2006;6(8):618-23.
26. Klonowski KD, Williams KJ, Marzo AL and Lefrancois L. Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor Expression and Memory CD8 T Cell Development. J Immunol. 2006;177(7):4247-51.
27. Marzo AL,Klonowski KD, Williams KJ, Lee SJ, Pham QM, and Lefrançois L. The location of CD8 T cell activation shapes the recall response to pathogens. J. Immunol. 2006; 177(10): 6738-6746.
28. Moore MW, Cruz AR, Lavake CJ, Marzo AL, Eggers CH, Salazar JC, Radolf JD. Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces IFN-{gamma} production. Infect Immun. 2007;75(4):2046-62.
29. Graham VA, Marzo AL and Tough DF. A role for CD44 in T cell development and function during direct competition between CD44+ and CD44- cells. Eur J Immunol. 2007;37(4):925-34.
30. Marzo AL and Lefrançois L. Cutting Edge: The functional plasticity of memory CD8 T cells is
dependent on location not phenotype. J Immunol. 2007; 179:36-40.
31. Allam A, Conze DB, Torchia MLG, Yagita H, Munitic I, Sowell RT, Marzo AL and Ashwell JD. The CD8 T cell memory state of readiness is actively maintained and reversible. Blood. 2009. 114(10):2121-30.
32. Tamson V. Moore, Bryan S. Clay, Caroline Ferreira, Jesse Williams, Magdalena Rogozinska, Judy L. Cannon, Rebecca A. Shilling, Amanda L. Marzo, and, Anne I. Sperling. Protective effector memory CD4 T cells depend on ICOS for survival. 2011. PLoS One. Feb 18;6(2):e16529.
33. Zloza A, Kohlhapp FJ, Lyons GE, Schenkel JM, Moore TV, Lacek AT, O'Sullivan JA, Varanasi V, Williams JW, Jagoda MC, Bellavance EC, Marzo AL, Thomas PG, Zafirova B, Polić B, Al-Harthi L, Sperling AI, Guevara-Patiño JA. NKG2D signaling on CD8⁺ T cells represses T-bet and rescues CD4-unhelped CD8⁺ T cell memory recall but not effector responses. Nat Med. 2012 Feb 26;18(3):422-8.
34. Nadine M. Lerret, Magdalena Rogozinska, Andrés Jaramillo and Amanda L. Marzo. Adoptive transfer of Mammaglobin-A epitope specific CD8 T cells combined with a single low dose of total body irradiation eradicates breast tumors. PLoS One. 2012;7(7):e41240. Epub 2012 Jul 20.
35. Lerret NM, Marzo AL. Adoptive-T-cell transfer combined with a single low dose of total body irradiation eradicates breast tumors. Oncoimmunology. 2013 2(2): e22731.
36. Ryan T. Sowell, Magdalena Rogozinska, Christine E. Nelson, Vaiva Vezys and Amanda L. Marzo. Cutting Edge. Generation of effector CD8 T cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J Immunol. 2014 Sep 1;193(5):2067-71.
37. Ryan T. Sowell and Amanda L. Marzo. Resident-memory CD8 T cells and mTOR: Generation, Protection, and Clinical Importance. Front Immunol. 2015. Feb 5:6:38.
38. Kohlhapp FJ, Huelsmann EJ, Lacek AT, Schenkel JM, Lusciks J, Broucek JR, Goldufsky JW, Hughes T, Zayas JP, Dolubizno H, Sowell RT, Kühner R, Burd S, Kubasiak JC, Nabatiyan A, Marshall S, Bommareddy PK, Li S, Newman JH, Monken CE, Shafikhani SH, Marzo AL, Guevara-Patino JA, Lasfar A, Thomas PG, Lattime EC, Kaufman HL, Zloza A. Non-oncogenic Acute Viral Infections Disrupt Anti-cancer Responses and Lead to Accelerated Cancer-Specific Host Death. Cell Rep. 2016 Oct 18; 17(4):957-965
Research
Immunological memory is the basis for long-lasting protective immunity. An important aspect of this line of defense is the class of immune cells known as CD8T lymphocytes. These cells are crucial for both clearance of viruses and limiting the growth of virally infected cells. The CD8 T cell response to virus results in the formation of a memory population of cells, which serves as a protective barrier against future insults by the same virus.
My lab is interested in understanding the mechanisms underlying the induction and maintenance of memory CD8+ T cells, the factors responsible for sustaining effector function and the mechanisms for their persistence. CD8+T lymphocytes are crucial for both clearance of intracellular pathogens and limiting the growth of virally infected cells and tumors. For both pathogens and tumors, the inability to generate functional memory CD8 T cells in the targeted tissue is one limitation of current vaccine strategies. After antigen exposure, CD8 T cells undergo massive clonal expansion and differentiate into effectors. Subsequently, a dramatic contraction phase occurs in which the majority of these effectors die. The end result is a population of memory CD8 T cells that survive this process which serve as a protective barrier against future insults and is the basis for long-lasting protective immunity. Despite tremendous advances in the characterization of memory T cells against pathogens and tumors in the last decade, we are still on the cusp of fully understanding the mechanisms that control and effect memory T cell generation and maintenance in different tissues. Memory T cells are endowed with unique properties that permit more vigorous and specific responses upon re-challenge to protect against pathogens and tumors. The challenge is to be able to not only increase the number of functional memory CD8 T cells but also to get them to the tumor or site of infection. Our laboratory is addressing this limitation by combinatorial therapy using agents that can increase the number, function and migratory capacity of memory CD8 T cells for bacterial and viral infections as well as for tumors.
Project 1: Determine the mechanisms by which mTOR regulates the maintenance of mucosal resident memory CD8 T cells at the initial site of pathogen entry.
The majority of viral infections are established through transmission across mucosal surfaces. However much of what we currently know about the generation and function of memory CD8 T cells is through the study of CD8 T cells found in the blood and secondary lymphoid tissues. Despite the fact that memory CD8 T cells in secondary lymphoid tissues and mucosal tissues originate from the same population of naïve precursors, they are functionally distinct. In the mucosa CD8 T cells express higher levels of Granzyme B, CD69, and express markers that confer them with the ability to traffic to and persist in specific sites. Successful control of infections that occur in mucosal tissues such as the gastrointestinal tract are thought to be associated with the presence of sustained tissue resident memory CD8 T cells that reside in the draining lymph nodes.
Project 2: Establish if we can increase HSV-2 specific effector memory CD8 T cells in the FRT by regulating the level of mTOR signaling using rapamycin.
The majority of viral infections in the FRT are established through transmission across mucosal surfaces that line the genital tract. However much of what we currently know about the generation and function of memory CD8 T cells is through the study of CD8 T cells found in the blood and secondary lymphoid tissues. Despite the fact that memory CD8 T cells in secondary lymphoid tissues and mucosal tissues originate from the same population of naïve precursors, they are functionally distinct. In the mucosa CD8 T cells express higher levels of Granzyme B, CD69, and express markers that confer them with the ability to traffic to and persist in specific sites. Successful control of infections that occur in the FRT, such as HSV-2, are thought to be associated with the presence of sustained tissue resident memory CD8 T cells that reside in the draining lymph nodes of the genital tract and the vaginal mucosal tissues.
Project 3: Establish the relationship between increasing tumor antigen load and the generation of tumor-specific effector memory CD8 T cells. One limitation of current cancer vaccine strategies is the inability to generate effective memory CD8 T cell responses. Our knowledge of how these anti-tumor CD8 memory T cells are generated and maintained in vivo following immunotherapy is limited. In response to vaccination, CD8 T cells expand, differentiate into effectors and then undergo contraction. The end result is a population of CD8 memory T cells that survive this process. The proposed research intends to elucidate the mechanism by which tumor-specific CD8 memory T cells are generated and maintained leading to rejection of poorly immunogenic tumors. Our long-term goal is to elucidate whether successful immunotherapy drives CD8 memory T cell differentiation and to identify the factors that influence this process. This proposal will investigate specific mechanisms that impact CD8 memory T cell induction during tumor growth (without adoptive transfer of tumor-specific CD4 T cells) as opposed to tumor rejection (with tumor-specific CD4 T cell help). The proposed project has implications for both current immunotherapies and for the better design of vaccines. Determining the interactions between cellular elements, the tumor microenvironment and potential modulators is an important step in a careful analysis of how memory CD8 T cells develop in tumor bearing mice.
Project 4: Determine the effect IL-15 has on the expression of co-inhibitory molecules on tumor infiltrating T cells from HNSCC patients. Head and neck squamous cell carcinoma (HNSCC) is a debilitating and deadly disease and is the seventh most common cancer worldwide. Approximately 600,000 new cases are diagnosed each year, including about 50,000 in the United States accounting for about 3% to 5% of all cancers in the U.S . HNSCC occurs most often in men in there 50s or 60s, although the incidence among younger individuals is increasing. The five-year survival rate of patients with head and neck cancer is about 60%. HNSCC is a disease that causes significant morbidity as it impacts highly critical functions of respiration, swallowing food and water as well as speech. The management of advanced HNSCC consists of multiple-modality therapies including surgery, radiation, and chemotherapy. Despite rigorous combination modalities cure rates only reach 30% for late stage disease . At this late stage of disease palliative surgery is often difficult and radiation and chemotherapy does not substantially improve survival rates in HNSCC patients. Prognosis for these patients remains poor, such that the median survival after recurrence is only approximately six months. Although in recent years significant advances have been made in targeted therapies, HNSCC recurrence, resistance to chemo-radiotherapy and cervical lymph node metastasis persist as the most important factors affecting the poor prognosis of patients with HNSCC. Therefore identification and characterization of the molecular mechanisms underlying HNSCC initiation and progression are required for timely diagnosis and developing effective treatment. Our study, in direct relevance to clinical application explores the synergistic potential in targeting a combination of IL-15 and co-inhibitory molecule blockade to elicit durable antitumor immunity and enhanced immunoreactivity of tumor antigen specific CD8+ T cells.