Immunotherapy has significant potential to treat cancer including lymphoma. However, immune dysfunction is a major barrier to achieving optimal clinical responses. Currently we do not fully understand the underlying mechanisms driving immune dysfunction in tumours and surrounding lymph nodes (LNs). Lymphomas like chronic lymphocytic leukaemia, develop in LNs and corrupt normal tissue and immune architecture. There is also emerging evidence that LNs draining other cancer types and associated tissues become corrupted by tumour factors. We hypothesise that cancer reprograms LN-resident fibroblasts and endothelial cells (stromal cells) and alters their immune-supporting interactions with key immune cell populations (e.g. T cells, dendritic cells, NK cells), that creates a pro-tumour and immunosuppressive niche.
The aims of this studentship include: Years 1-2: a) perform a single-cell and spatial transcriptomic analyses of lymphoma burdened LNs, b) bioinformatically predict the molecular interactions occurring between lymphoma-corrupted stromal cells and key leukocyte populations, c) high resolution of imaging to molecularly define tumour-stroma-immune crosstalk in lymphoma LNs; Years 2-4: d) functionally model immune inhibitory crosstalk including a focus on immune checkpoint molecules and immune-engaging bispecific antibodies (AZ immunotherapy pipeline). This partnership between King’s College London, KCL with AstraZeneca (AZ) will offer opportunities to learn cutting-edge single-cell and spatial transcriptomics, bioinformatics (KCL, AZ), confocal microscopy (core Nikon Imaging Centre, KCL) and run Industry-standard spatial transcriptomic/protein and immunotherapy studies (AZ).
Understanding immunosuppressive stroma-immune networks in lymphoma-burdened lymph nodes to optimise immunotherapy
Representative Publications
Co-1A
1. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma. Apollonio B, Spada F, Petrov N, Cozzetto D, Papazoglou D, Jarvis P, Kannambath S, Terranova-Barberio M, Amini RM, Enblad G, Graham C, Benjamin R, Phillips E, Ellis R, Nuamah R, Saqi M, Calado DP, Rosenquist R, Sutton LA, Salisbury J, Zacharioudakis G, Vardi A, Hagner PR, Gandhi AK, Bacac M, Claus C, Umana P, Jarrett RF, Klein C, Deutsch A, Ramsay AG. J Clin Invest. 2023 Jul 3;133(13):e166070. doi: 10.1172/JCI166070.
2. Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial. Papazoglou D, Wang XV, Shanafelt TD, Lesnick CE, Ioannou N, De Rossi G, Herter S, Bacac M, Klein C, Tallman MS, Kay NE, Ramsay AG.Blood. 2024 Jan 4;143(1):57-63. doi: 10.1182/blood.2023020554.
3. Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy. Ioannou N, Hagner PR, Stokes M, Gandhi AK, Apollonio B, Fanous M, Papazoglou D, Sutton LA, Rosenquist R, Amini RM, Chiu H, Lopez-Girona A, Janardhanan P, Awan FT, Jones J, Kay NE, Shanafelt TD, Tallman MS, Stamatopoulos K, Patten PEM, Vardi A, Ramsay AG. Blood. 2021 Jan 14;137(2):216-231. doi: 10.1182/blood.2020006073.
Co-1B
1. Abdul-Jawad, S., Baú, L., Alaguthurai, T., …, Hayday, A. C., Patten, P. E. M., & Irshad, S. (2021). Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients. Cancer Cell, 39(2), 257–275.e6. https://doi.org/10.1016/j.ccell.2021.01.001
2. Patten, P. E. M., Ferrer, G., Chen, S. S., et al. (2021). A Detailed Analysis of Parameters Supporting the Engraftment and Growth of Chronic Lymphocytic Leukemia Cells in Immune-Deficient Mice. Front Immunol, 12, 627020. https://doi.org/10.3389/fimmu.2021.627020
3. Friedman, D., Mehtani, D. P., Vidler, J. B., Patten, P. E. M., & Hoogeboom, R. (2024). Proliferating CLL cells express high levels of CXCR4 and CD5. Hemasphere, 8(12), e70064. https://doi.org/10.1002/hem3.70064