Immune Regulation and Tumour Immunotherapy

The Immune Regulation and Tumour Immunotherapy Group aims to investigate the interplay between the immune system and cancer throughout tumour progression and immunotherapy. 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.

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 known about the biology of tumour-reactive CD4+ T cells during tumour progression and cancer immunotherapy.

Research

Our aim is 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. Moreover, we are interested in how the function and plasticity of tumour-reactive CD4+ T cells and the innate immune compartment 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). In addition, 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 anti-tumour 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.

Mapping out the T Cell Landscape in Solid Tumours

The contribution of neoantigen reactive T cells to anti-cancer immunity has become increasingly well-established over the last decade. A key role for neoantigen-driven tumour recognition in humans is supported by the observations that i) patients with greater non-synonymous mutational burden (TMB) exhibit favourable clinical response to checkpoint blockade, ii) neoepitope-specific T cells can be detected in clinical samples, iii) adoptive T cell therapies that elicit radiographic responses contain neoantigen reactive T cell clones and iv) footprints of immune escape are enriched in tumours with an elevated neoepitope load. However, the mechanisms underpinning neoantigen-specific T cell responses remain poorly characterized. Therefore, understanding how the neoantigen-driven T cell response is orchestrated at the cellular and molecular level may optimise cell therapies, identify novel immunotherapy targets and define clinically relevant biomarkers. Our team is working together with several clinical trials and biobanks including TRACERx (for lung cancer) and APADTER (renal cancer), DECIPHER (prostate) and Glioblastomas to understand the different T cell states and populations in these cancers and how TCR heterogeneity and T cell exhaustion correlates with poor clinical outcomes and to better understand mechanisms of response and resistance to immune checkpoint blockade.

Understanding the Mechanisms of Action of Immunomodulatory Agents

Our lab uses several mouse cancer models including lung, melanoma, colorectal and brain cancers to understand the mechanisms of action of immunomodulatory agents. When tumours are established, we administrate a variety of immunomodulatory agents and evaluate their tumour control efficacy and investigate the impact of these therapies on the immune landscape observed by high-dimensional flow cytometry. Using these models, we have unveiled the role of Fc/FcReceptor (FcR) interactions in the activity of immune modulatory monoclonal antibodies. We demonstrated a key role for antigen density and activating FcR in promoting depletion of tumour infiltrating regulatory T cells by anti-CTLA-4 antibodies (Arce Vargas et al., 2018) and a new anti-CD25 antibody developed by our team (Arce Vargas et al., 2017), currently under clinical evaluation (NCT04158583, clinicaltrials.gov).

Our team is now working to understand the role of FcγR-expressing cells on anti-CTLA-4 and anti-PD-1 treated tumours and further evaluate the function of FcγR engagement with agonistic antibodies.

Cytotoxic Activity by Tumour Reactive CD4+ T Cells and their Potential Application in Tumour Immunotherapy

In addition to classical helper or regulatory activity, tumour-infiltrating CD4+ T cells can also acquire cytotoxic potential, marked by expression of Granzyme B. These cytotoxic CD4+ T cells directly kill tumour cells in an MHC-II-dependent manner, and promote rejection of established tumours in murine models of melanoma and sarcoma. Recently, we showed that tumour-infiltrating CD4+ T cells acquire cytotoxic potential in response to IL-2 signalling, and require the transcription factor Blimp-1. Furthermore, differentiation of cytotoxic CD4+ T cells in tumours is limited by a high infiltration of suppressive regulatory T cells (Tregs), which act as a sink for IL-2. Currently, we are investigating the role of Blimp-1, and other transcription factors, in regulating CD4+ T cell differentiation and function in tumours.

Publications

1. Solomon I, Amann M, Goubier A ... Quezada SA. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer. 2020 Dec;1(12): 1153-1166.
2. Śledzińska A, Vila de Mucha M, Bergerhoff K ... Quezada SA. Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells. Immunity. 2020 Jan 14;52(1): 151-166.e6.
3. Ghorani E, Reading JL, Henry JY ... Quezada SA. The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Nat Cancer. 2020 May;1(5): 546-561.
4. Joshi K, de Massy MR, Ismail M ... Quezada SA, Chain B. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat Med. 2019 Oct;25(10): 1549-1559. Erratum in: Nat Med. 2020 Jul;26(7): 1148.
5. Quezada SA, Peggs KS. Lost in Translation: Deciphering the Mechanism of Action of Anti-human CTLA-4. Clin Cancer Res. 2019 Feb 15;25(4):1130-1132.
6. Joshi K, Chain BM, Peggs KS, Quezada SA. The "Achilles' Heel" of Cancer and Its Implications for the Development of Novel Immunotherapeutic Strategies. Cold Spring Harb Perspect Med. 2018 Jan 2;8(1): a027086.
7. Ghorani E, Rosenthal R, McGranahan N ... Quezada SA. Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma. Ann Oncol. 2018 Jan 1;29(1): 271-279.
8. Arce Vargas F, Furness AJS, Litchfield K ... Quezada SA. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer Cell. 2018 Apr 9;33(4): 649-663.e4.
9. Reading JL, Gálvez-Cancino F, Swanton C, Lladser A, Peggs KS, Quezada SA. The function and dysfunction of memory CD8+ T cells in tumor immunity. Immunol Rev. 2018 May;283(1): 194-212.
10. Wong YNS, Joshi K, Khetrapal P ... Quezada SA. Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment. J Exp Med. 2018 Nov 5;215(11): 2748-2759.