UCL Cancer Institute

Immune Regulation and Tumour Immunotherapy Group (IRTI)



Group Leader: Dr Sergio A Quezada PhD





Our group uses transplantable and autochthonous mouse models of cancer to investigate the in vivo interplay between the immune system and cancer throughout tumour progression and immunotherapy. Our aim to identify and target the most relevant cellular and molecular pathways restricting the activation of tumour-reactive lymphocytes, their access to the tumour site, and their activity within the tumour microenvironment.


Research

The use of our own immune system to specifically target cancerous cells has become a promising approach in the fight against cancer. However, anti-tumour immunity is tightly regulated by cellular and molecular circuits that prevent self and tumour destruction and significantly limit the efficacy of existing therapies.

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Fig 1  
The intra-tumour balance of effector and regulatory T cells: The infiltration of tumours by different subsets of lymphocytes can be initially affected by the activation state of the tumour vasculature as well as by the tumour microenvironment. Changes in the activation state of T cells, their infiltration capacity or in the tumour microenvironment itself will tip the balance between tumour elimination and tumour escape.



CD4+ T cells play a key role in the regulation of immune responses to self and foreign antigens, differentiating into various subsets of helper and regulatory T cells and instructing the function of CD8+ T cells, NK cells and macrophages. Nonetheless, little is still know about the biology of tumour-reactive CD4+ T cells during tumour progression and cancer immunotherapy. Most importantly, we recently demonstrated that tumour-reactive CD4+ T cells can also acquire granzyme-dependent cytotoxic activity and directly target and kill tumour cells in vivo.

fig

Fig 2   Tumours can be predominantly infiltrated by regulatory T cells instead of effector cells which favours tumour escape instead of elimination.



Our group is interested in how the function and plasticity of tumour-reactive CD4 T cells is regulated by the tumour microenvironment and by immune co-inhibitory (e.g. CTLA-4 and PD-1) and co-stimulatory signals (e.g. GITR, OX40, CD27). As well, we are interested in understanding how these regulatory circuits control the efficacy of cellular vaccination and adoptive cell transfer strategies and how can they be manipulated to induce potent antitumor immunity. These studies will not only inform the basic understanding of the immune response to malignancies but, in the context of the UCL Cancer Institute, will be used as a platform for the development of novel translational strategies in the clinic.

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Fig 3  
Blockade of immune-regulatory receptors such as CTLA-4 enhances T cell activation, favours the accumulation of effector cells within the tumour and tilts the balance towards tumour elimination.



Our group works in close collaboration with Dr Karl Peggs’ Stem Cell Transplantation and Cellular Immunotherapy group in all aspects of our research but most critically we believe that our collaborative efforts will facilitate the application of our discoveries in clinical settings.

FIG

Fig 4   Effective vaccination strategies and tumour rejection correlate with activation of the tumour vasculature (ICAM up-regulation) and T cell infiltration.



The research projects being currently developed in the laboratory include:

  1. Studying the changes in the activity of helper and regulatory tumour-reactive CD4+ T cells during tumour progression and immunotherapy. We are analysing the changes on the CD4+ T cell compartment in response to the tumour microenvironment and immune-stimulatory regimes using an inducible mouse melanoma model that better represents human disease.
  2. Studying how different immune cells and the tumour microenvironment affect the tumour vasculature and the impact of this interplay in tumour progression and its response to immunotherapy.
  3. Design of tumour cell-based vaccines that prime effector T cell responses with no activation of regulatory cells. Our mechanistic studies have demonstrated that cellular vaccinations can efficiently prime effector T cell responses but that the accompanying expansion of Foxp3+ and IL-10 secreting regulatory T cells significantly limit therapeutic activity. We are currently designing novel vaccination strategies that favour induction of effector activities without their regulatory counterpart.
  4. Studying the cellular and molecular events controlling acquisition of cytotoxic activity by tumour reactive CD4+ T cells and their potential application in tumour immunotherapy. Although the presence of CD4+ CTL have been previously described in responses to viral infections, their activity and potential relevance in cancer has been completely understudied. We will use different mouse models as well as human samples to study the basis of their activity and their potential application as a tool in the fight against cancer.

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Fig 5   Combinatorial approaches incorporating radiation therapy, CTLA-4-blockade and transfer of tumour reactive CD4+ T cells (Trp1) results in differentiation of CD4+ T cells into Granzyme+ effectors capable of infiltrating and rejecting large, vascularized tumours.



 

Group Leader


Dr Sergio A Quezada PhD


Team Members


Collaborators

 





 

Selected Publications


Quezada SA, Peggs KS. 2011. Tumor-reactive CD4(+) T cells: plasticity beyond helper and regulatory activities. Immuno-therapy 3:915-917. Pubmed

Quezada SA, Peggs KS, Simpson TR, Allison JP. 2011. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication. Immunological Reviews 241:104-118. Pubmed

Peggs KS and Quezada SA. 2010. Ipilimumab: attenuation of an inhibitory immune checkpoint improves survival in metastatic melanoma. Expert review of anticancer therapy 10:1697-1701. Pubmed

Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA et al. 2010. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207:637-650. Pubmed

Peggs KS*, Quezada SA*, Chambers CA, Korman AJ and Allison JP. 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206:1717-1725. *contributed equally. Pubmed

Quezada SA*, Peggs KS*, Simpson TR, Shen Y, Littman DR and Allison JP 2008. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 205:2125-2138. *contributed equally. Pubmed

Peggs KS, Quezada SA and Allison JP. 2008. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 224:141-165. Pubmed

Quezada SA*, Peggs KS*, Curran MA and Allison JP. 2006. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935-1945. *contributed equally. Pubmed