Figure 1. CAR-T cells versus the solid tumor microenvironment (from Foeng et al 2022).
It is now no secret that chimeric antigen receptor (CAR)-T cell therapy has produced remarkable results in treating some blood cancers. In May 2022 the world’s first paediatric recipient of CAR-T cell therapy for acute lymphoblastic leukaemia, Emily Whitehead, was declared ‘cured’ after 10 years cancer-free.
This success so far has not been replicated in CAR-T cell therapies for solid cancers, with these cancers presenting numerous challenges not present in blood cancers. One of the major obstacles being the successful trafficking of CAR-T cells into tumours.
In some studies, less than 1-2% of adoptively transferred T cells were found to be able to infiltrate solid tumours.
The immunosuppressive tumour microenvironment
A tumour is more than just a group of cancer cells but rather develops as a ‘tumour microenvironment’ (TME) – a highly complex and continuously evolving entity.
Consisting of many different cells all packed in a densely barricaded and hostile tissue architecture, the TME plays an important role in cancer progression (Foeng et al 2022, Anderson & Simon 2020).
The composition of the TME varies between different tumours but mostly consists of immune cells, stromal cells (connective tissue cells), blood vessels and extracellular matrix (Anderson & Simon 2020).
TMEs are infiltrated with a diverse array of adaptive and innate immune cells. Depending on the context, these immune cells can either suppress or promote tumour growth (Foeng et al 2022, Anderson & Simon 2020).
The TME presents not only a physical barrier to CAR-T cells but creates an often immunosuppressive environment that dampens the ability of immune cells to track to and kill cancer cells.
In order to develop successful solid tumour CAR-T cell therapies, these challenges need to be overcome.
This is where chemokines come in…
Chemokines and their chemokine receptors
Chemokines are small, secreted proteins that play a vital role in cell migration and movement. There are 47 known chemokines and 20 known chemokine receptors, allowing for a high degree of specificity in the movement of cells to particular sites (Rot & von Andrian 2004).
For a cell to respond to a chemokine, it must express a complementary chemokine receptor. When a chemokine binds to its receptor, a signalling cascade is created that results in the activation of molecules involved in cell adhesion and the development of cellular projection, ultimately leading to cell movement (Foeng et al 2022, Rot & von Andrian 2004, Lauffenburger & Horwitz 1996).
The receptors expressed on a cell determine which tissue or specific site a cell will migrate into. For example, cells that express the chemokine receptor CCR7 migrate to lymph nodes where complementary chemokines to CCR7 (CCL19 and CCL21) are expressed (Comerford et al 2013).
In the TME, chemokines can be expressed by tumour cells, stromal cells and infiltrating leukocytes (white blood cells surrounding the tumour and inside the tumour). As well as mediating trafficking into the TME, chemokines may directly regulate tumour cell proliferation, invasiveness and metastasis.
Indeed, the chemokine system largely orchestrates the choreographed migration of a wide variety of cells into the TME – with important consequences for driving or inhibiting tumour growth (Foeng et al 2022).
Harnessing the chemokine system to improve CAR-T cell homing
Harnessing the chemokine system has been identified as an attractive way to improve the trafficking of CAR-T cells into solid tumours (Foeng et al 2022).
As well as improving the ability of CAR-T cells to get in closer proximity to and destroy cancer cells, directly trafficking CAR-T cells into tumours provides significant safety advantages.
A better understanding of the specific chemokine expression profile in the TME across different cancers may inform which chemokine axes can be used to enhance CAR-T cell trafficking.
It is hoped that this will lead to the development of therapeutic CAR-T cells that efficiently track to and specifically recognise a broad range of malignant cells within solid tumours, producing effective CAR-T cell therapies for many solid cancers.
To learn more about this, Carina Biotech researchers Dr Jade Foeng and Professor Shaun McColl have recently published a review article on harnessing the chemokine system to improve CAR-T cell homing in Cell Reports Medicine. The full article can be found here.
This article was informed by a number of scientific journal articles:
Foeng, J., Comerford, I. & McColl, S.R. (2022). Harnessing the chemokine system to home CAR-T cells into solid tumours (review). Cell Reports Medicine 3, 100543, March 15 2022: https://www.cell.com/cell-reports-medicine/pdf/S2666-3791(22)00043-X.pdf
Anderson, N.M. & Celeste Simon, M. (2020). The tumor microenvironment. Curr Biol 2020 Aug 17; 30(16): R921-R925, https://pubmed.ncbi.nlm.nih.gov/32810447/
Rot, A. & von Andrian, U.H. (2004). Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol. 2004;22:891-928: https://pubmed.ncbi.nlm.nih.gov/15032599/
Lauffenburger, D.A. & Horwitz, A.F. (1996). Cell migration: a physically integrated molecular process. Cell 1996 Feb 9;84(3): 359-69: https://pubmed.ncbi.nlm.nih.gov/8608589/
Comerford, I., Harata-Lee, Y., Bunting, M.D., Gregor, C., Kara, E.E & McColl, S.R. (2013). The myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system. Cytokine Growth Factor Rev. 2013 June; 24(3): 269-83: https://pubmed.ncbi.nlm.nih.gov/23587803/