Cancer Tumour Associated Macrophages (TAMs) What is a tumour? -a pathological lesion characterized by progressive and uncontrolled proliferation of cells There are hallmarks of cancer, the sets of capabilities a tumour has to acquire to keep growing and progress. -sustaining proliferative signalling -evading growth suppressors -avoiding immune destruction -enabling replicative immortality -activating invasion and metastasis -inducing angiogenesis -resisting cell death -deregulating cellular energetics Tumour Micro-environment: Tumour= tumour cells + tumour STROMA -Cancer associated fibroblasts= remodelling EM to help tumour cells to migrate and invade + release growth factors -Blood vessels: endothelial cells and pericytes form new BV to provide O2 and nutrients -Resident and Bone marrow derived haematopoietic cell Tumour Angiogenesis and Invasion -low O2, hypoxia, release growth factors for endothelial cells to induce blood vessels to feed for tumour growth. There are macrophages sitting at the tip of sprouting BV enabling them to fuse. BV vascularize tumour. Now the tumour cells can migrate towards BV and intravasate and grow lymphatic vessels, disseminate to distal region and for metastasis in other organs. -there's a need for the tumour to interact with macrophages and intravasate to disseminate The Tumour Micro-environment 1) Heterogenous: several subpopulation within each tumour different composition in -different tumour types -different regions within the same tumour -different stages of the same tumour 2) Signalling complexity: constant cross talk between the different cell types. Each cell can release factors that can be bound by other cells if they have the specific receptors. ff) Evolution: both neoplastic cells and the stromal cells around them change progressively. Back and forth reciprocal interaction- change phenotype of different cells present in tumour microenvironment. -heterotypic interactions -tumour progression to different stage and malignancy The STROMA is composed of many different normal cell types (not mutated)
Immune cells functions 1) Defence- identification and protection against pathogenic microorganisms and toxins 2) Autotolerance- recognition of own tissues and keeping tolerance to them ff) Immune surveillance- identifying and removing the old, damaged and otherwise changed cells Tumour mutational burden leads to neoantigen production, neoantigens are captured and processed by the antigen presenting cells (APCs- macrophages/ dendritic cells), APCs present neoantigens to activate cytotoxic T cells. Resolution of inflammation -when there's too much inflammation, it damages the tissue so immune system stops this to avoid chronic inflammation -if there's too much immune suppression, it's not taking care of the infection which leads to chronic inflammation because immune system keeps trying to fight the infection but cannot win due to increase immune suppression Immune surveillance of tumours (3 stages) 1) Elimination: the pre-neoplastic lesion where immune suppression comes in to eliminate (mostly M1 macrophages, pro inflammatory contributes to immune response against tumour) 2) Equilibrium: it's a complicated phase. Attacking cell that expresses a specific antigen. Tumour cells are heterogenous, all different as they proliferate, accumulate different mutation. Some cells can be recognised by the immune system, but some cannot as they are 'newly' expressed antigen. Immune system eliminates cells it recognises but those that it doesn't will expand and grow.