Foakes, Callum; (2024) The immunoregulatory function of fibroblasts in solid tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer-associated fibroblasts (CAFs) surround and infiltrate the tumour microenvironment (TME) of solid tumours. CAFs engage in crosstalk with tumour and immune cells, influencing cancer morphology and progression. CAFs have pleiotropic roles in anti-tumour immunity, including secreting immunosuppressive cytokines such as TGFβ and IL10, which support tumour survival and immune evasion. Conversely, a chronically inflammatory environment—such as that found in autoimmune diseases or cancer—can drive fibroblasts to differentiate into a reticular phenotype, enhancing immune cell trafficking, organisation, and activity. These CAFs resemble fibroblastic reticular cells (FRCs) found in lymphoid tissues, including lymph nodes. FRCs are specialised fibroblasts that organise lymphocytes into distinct compartments, facilitating antigen presentation and lymphocyte activation to promote immune responses, including anti-tumour immunity. Therefore, I hypothesised that FRCs could bolster anti-tumour responses if transplanted into tumours. Strikingly, co-transplanting FRCs with tumour cells significantly suppressed tumour growth compared to tumour cells alone. Flow cytometry and immunofluorescent imaging revealed that FRCs recruited B and T cells to form intratumoural aggregates. Subsequent analyses investigate the functional determinants of FRCs in immune cell recruitment and tumour suppression. In vivo analysis of newly generated FRC KO lines revealed that Ccl21, Cxcl13 and Icam1 were required for FRC-mediated immune cell recruitment and tumour growth suppression. These findings reveal novel functions of FRCs and highlight key proteins critical for the development and function of lymphoid structures in anti-tumour immunity, establishing a new framework to investigate these mechanisms across various inflammatory diseases and tissue types. Chapter 5 explores how local signals can induce phenotypic changes in CAFs toward a more FRC-like phenotype, aiming to regulate immune recruitment and organisation within tumours and enhance anti-tumour immunity without direct FRC injection. Tumour cell lines overexpressing soluble factors related to lymphocyte recruitment, activation, and lymphoid tissue formation showed that increased levels of CCL21, CXCL13, IL15, and LTα within the TME elevated immune cell numbers and suppressed tumour growth. These insights have broad implications for fibroblast biology and clinical immunotherapies.

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