This essay covers all the content of lecture 7 of Immunology of Human Disease. The essay question is: Discuss the fundamental hallmarks of cancer, elucidate the challenges presented by the tumour microenvironment in relation to immune responses, and delineate the prerequisites for an efficient T ce...
A. Discuss the fundamental hallmarks of cancer, elucidate the challenges presented by the
tumor microenvironment in relation to immune responses, and delineate the
prerequisites for an efficient T cell-mediated immune response.
a. Explain the basic hallmarks of cancer, focusing on key characteristics that
distinguish cancer cells from normal cells.
b. Analyse the obstacles posed by the tumor microenvironment to effective immune
responses against cancer.
c. Outline the essential requirements for a successful T cell immune response against
cancer and highlight examples illustrating the mechanisms of immune suppression
in the context of cancer
The hallmarks of cancer include genetic instability, sustained growth signalling, resisting
programmed cell death and angiogenesis. In the tumour microenvironment, co-inhibitory
ligands are massively up-regulated and the chronic persistent antigen stimulation causes
constant TCR stimulation and T cell exhaustion and T cell mitochondria becomes
dysregulated. In this essay, we will analyse the TME in relation to immune responses and
outline the requirements for a successful T cell response against cancer.
Solid tumours can be extremely disorganised with many accessory cells supporting the
growth of tumour cells such as cancer associated fibroblasts (CAF), mesenchymal stem cells
(MSCs) and the ECM. These help the tumour grow out, making it more difficult to treat the
bigger it grows. CAFs are important in shaping the complex matrix milieu and the mechanism
of the tissue in which the tumour grows and metastasises. Also, myeloid cells thrive in the
TME because of abundant cytokines, chemokines and growth factors. This TME is particularly
challenging for T cells because of the low nutrients and oxygen, the expression of co-inhibitory
molecules and infiltration of regulatory molecules. The TME plays a key role in determining
the tumour immunotype such as it may be immune inflamed with presence of abundant
immune infiltrate, immune excluded where T cells infiltrate is limited to the tumour stroma
and immune desert where there is no immune infiltrate. The TME also prevents the robust
up-regulation of co-stimulatory molecules on APCs leading to sub-optimal T cell activation.
In response to tumours, cancer cells need to be recognised by the innate immune system such
as a cancer antigen is released and recognised, priming and activating T cells. DCs present the
antigen to the T cell and therefore their role and activation in the cancer-immunity cycle is
important. Priming of naïve T cells requires four signals because they are very potent and
need to be tightly controlled. APC-T cells interaction influences signal 1 and 2, determining
the efficiency of T cell response. Signal I is stabilised by CD8+ T cell interaction with MHC I and
CD4+ T cell interaction with MHC II, increasing the signal delivered by the APC. The tumour
antigen presented may either by a tumour associated antigen or a tumour specific antigen.
This signal is mediated by the TCR via its interaction with the MHC. Signal 2 is the co-
stimulation of T cells via for example CD28. CD28 facilitates T cell survival, metabolism and
cytokine production. It strengthens signal 1 and induces cytokine production such as IL-2 for
T cell growth. Co-inhibitory molecules can interfere with CTLA-4 and PD-1 to control and
calibrate T cell response. Negative signal 2 molecules are increased after the activation of T
cells, outcompeting positive signals and regulating the extent and duration of T cell activation.
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