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Antigen Presentation and T Cell Immunity

T cells play a pivotal role in the control and clearance of tumours. Evidence is accumulating that both CD4+ helper and CD8+ killer T cells frequently recognize neoantigen peptides derived from proteins encoded by mutated genes in tumours. This provides an exciting new rationale to therapeutically induce or boost these anti-tumour T cell responses to treat patients with previously incurable cancers.

Dendritic cells (DCs) control these T cell responses. We have identified multiple populations of DCs with unique surface antigen expression that possess the ability to present cutaneous tumour antigen to T cells, raising the possibility that a complex division of labour exists amongst DCs responsible for immunosurveillance of the skin. This concept is being further examined so that it can be exploited for optimal delivery of vaccine antigen to the skin to promote enhanced anti-tumour T cell immunity. These vaccines will be used in conjunction with standard cancer treatments such as surgery, chemotherapy and radiotherapy as well as clinically approved antibodies that "take the brakes" off T cell immunity to "accelerate" tumour clearance. 

Natural Killer Cell Immunotherapy

Due to their ability to target a wide range of different cancers, natural killer (NK) cells are ideal candidates for immunotherapy. Clinically, both increased NK cell activity and NK cell infiltration of tumour sites has been associated with reduced risk of cancer and better prognosis. In recipients of allogeneic haematopoietic cell transplantation, NK cell alloreactivity has been associated with reduced leukaemic relapse, enhanced engraftment and reduced graft versus host disease. It's becoming increasingly clear that subsets of NK cells exist that differ in their capacity to lyse targets, produce cytokines, proliferate and survive. We, and others, have demonstrated that cytomegalovirus (CMV) infection has the ability to reconfigure the NK cell compartment and promote the expansion of functionally distinct subsets. So far, this phenomenon has been demonstrated to occur only with CMV infection and the mechanisms driving it remain unknown. Our previous research has characterised several subsets of NK cells that expand in the context of CMV infection. These NK cells display a mature phenotype, have increased functional capabilities, increased potential to mediate antibody dependent responses, increased survival capacity and the potential to be long lived. Clinically, CMV infection has been associated with reduced risk of leukaemic relapse and improved overall survival in transplant recipients. This research program focuses on determining how best to manipulate the NK cell compartment to generate the best NK cell subsets capable of eliminating cancer and gain an enhanced understanding of the mechanisms responsible for improved NK cell anti-tumour immunity. These findings will provide the foundation for the development of novel immune based therapies that can be utilised in the clinic to treat patients with cancer and improve overall survival.

Enhancing Tumour Immunity with Type I Interferons

Immunity commonly observed during acute viral infection is identical to what we would like to induce and sustain against cancer. Type I interferons (IFN-I) are one of the first cytokines produced during a viral infection and are responsible for directly and indirectly modulating the anti-viral immune response. Thus, it is logical that IFN-I has the potential to enhance anti-tumour immunity. However, systemic administration of IFN-I to cancer patients has not dramatically improved overall survival. This treatment has been limited to the use of only one subtype, IFN-a2. Considering 13 additional subtypes exist, we are investigating whether other IFN-I subtypes have an effect against a broad range of cancer types.

Wylie B, Seppanen E, Xiao K, Zemek R, Zanker D, Prato S, Foley B, Hart PH, Kroczek RA, Chen W and Waithman J. Cross-presentation of cutaneous melanoma antigen by migratory XCR1+CD103- and XCR1+CD103+ dendritic cells. Oncoimmunology, 2015 in press

Vavis S, Waithman J, Wood FM, Fear MW, Fear VS. The immune response to skin trauma is dependent on the etiology of injury in a mouse model of burn and excision. J Invest Dermatol 2015 in press

Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes T, Han H, Chiang S, Foley B, Mattsson K, Larsson S, Schaffer M, Malmberg K-J, Ljunggren H-G, Miller JS and Bryceson YT. Cytomegalovirus Infection Drives Adaptive Epigenetic Diversification of NK Cells with Altered Signaling and Effector Function. Immunity, 2015;43:443-456

Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Ross JA, Weisdorf DJ, Walcheck B, Vallera DA and Miller JS. Targeting Natural Killer cells to Acute Myeloid Leukemia with a CD16x33 bispecific killer cell engager (BiKE) and ADAM17 inhibition to overcome inhibitory signals Clinical Cancer Research, 2013;19:3844

Wei J*, Waithman J*, Xiao K, Oveissi S, Chen W. Optimal conditions required for influenza A infection enhanced cross-priming of CD8+ T cells specific to cell-associated antigens. Immunol Cell Biol. 2013; 91(9):576-582.

* These authors contributed equally to this work

Waithman J, Zanker D, Xiao K, Oveissi S, Wylie B, Ng RL, Togel L and Chen W. Resident CD8+ and migratory CD103+ dendritic cells control CD8 T cell immunity during acute influenza infection. PLoS One 2013; 8(6):e66136

Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, Anasetti C, Weisdorf DJ and Miller JS. Human cytomegalovirus (CMV)-induced memory-like NKG2C+ NK cells are transplantable and expand in vivo in response to recipient CMV antigen. Journal of Immunology. 2012;189(10):5082-5088

Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, Lopez-Vergès S, Lanier LL and Miller JS. Cytomegalovirus Reactivation after Allogeneic Transplantation Promotes a Lasting Increase in Educated NKG2C+ Natural Killer Cells with Potent Function. Blood, 2012; 119:2665-74 (highlighted in editorial)

Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, Weisdorf DJ and Miller JS. NK Cell Education after Allogeneic Transplantation: Dissociation Between Recovery of Cytotoxic and Cytokine-producing Functions Blood2011; 118:2784-92

Bedoui S*, Whitney PG*, Waithman J*, Eidsmo L, Wakim L, Caminschi I, Allan RS, Wojtasiak M, Shortman K, Carbone FR, Brooks AG, Heath WR. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol. 2009; 10(5):488-95.

* These authors contributed equally to this work

Research Staff

Dr Bree Foley

Geraldine Brizard (Research Assistant)

Ben Wylie (PhD Candidate)

Anthony Buzzai (PhD Candidate)

Tenielle George (PhD Candidate)

Chelsea Wilson (Honours Student)