Concept of cancer immunosurveillance and its influence on cancer immunotherapy

approaches

The immune system, according to the concept of immunosurveillance, is capable of

identifying and eliminating the most of cancer precursors. Immunoselection is a process by
which cancer cells evade immune surveillance by vigorously regulating the immune system
and identifying non-immunogenic tumour cell variability (which is now called
immunosubversion).

The development of cancer is halted by a number of tumor-suppressing mechanisms, many of

which function in a cell-intrinsic manner. Oncogenes can activate the DNA-damage
responses, which controls pre-malignant tumors by activating a number of different
molecules. These molecules include DNA-damage sensors such as ATM (ataxia-
telangiectasia mutated) and ATR (ATM and Rad3 related), checkpoint kinases such as CHK1
(checkpoint kinase 1 homologue) and CHK2, and the tumor-suppressor protein p ATM,
CHK2, and ATR can also end up causing cancerous cells to express ligands for NKG2D
(natural-killer group 2, member D), which could trigger an immune surveillance response.

The immunological features of tumour cells are impacted by every one of the seven well-
known hallmarks of cancer. Tumors could first develop their own growth signals by
developing autocrine and paracrine growth molecules with immunosuppressive
characteristics. Second, antigrowth signals like transforming growth factor- that result in
local immunosuppression no longer have the same effect on tumours. Third, in order to avoid
apoptosis and prevent caspase activation, tumours overexpress mitochondrial cell-death
inhibitors, which are probable tumour antigens (which is also needed for immunogenic cell
death). Fourth, increased p53 mutation and TERT (telomerase reverse transcriptase)
expression, two potential tumour antigens, are associated with unrestricted replication. Fifth,
sustained angiogenesis entails the production by tumours of angiogenic chemicals, such as
vascular endothelial growth factor, which inhibit dendritic-cell development and T-cell
activation. Sixthly, modifications in the immunological characteristics of tumours are related
to both positive and negative local infiltration and metastasis. The seventh feature modifies
the tumour cell's characteristics and creates a local immunosuppressive system that shuts
down innate and adaptive cytolytic effector proteins in order to prevent immune recognition.

TIL therapy for melanoma: To increase melanoma-specific T-cell responsiveness, stage IV

melanoma sufferers have received treatment with significant dosages of ex vivo enhanced
tumour-infiltrating T cells (TIL). TIL therapy resulted in a 50% RECIST (Response
Evaluation Criteria in Solid Tumours) clearance rate in clinical trials conducted in two
distinct cities. Regardless of the fact that unfractionated TIL products used for therapy often
contain both CD4+ and CD8+ T cells, cell therapy employing CD8-enriched TIL products
has also been shown to produce clinical responses. It is conceivable to speculate that the
ability of cytotoxic CD8+ T cells to kill cancer cells after T cell checkpoint suppression or
TIL therapy is at least somewhat accountable. The most patient-specific type of cancer
immunotherapy currently known is ex vivo boosted autologous T cell therapy. This treatment
strategy either involves the adoptive transplantation of tumour invading lymphocytes (TIL)
that have been produced from a resected lesion or the infusion of genetically modified
PBMCs that produce a newly inserted TCR. TIL therapy has thus far demonstrated very
promising clinical action, with an estimated 50% response rate seen in trials at numerous
clinical centres. It has been established that the infusion of CD8+-enriched TIL leads to
favourable clinical outcomes and that the quantity of CD8+ T cells administered controls the
effectiveness of TIL therapy.

Immune checkpoint inhibition: Immune checkpoint suppression, which does include immune
system response against high-dose IL-2 therapy, cytotoxic T-lymphocyte-associated protein 4
(CTLA4), adaptive T-cell immunotherapy, or programmed cell death 1 (PD-1), is one way
that anti-tumor T-cell responses can control the clinical progression of cancer. T cells often
do not, however, stop the progression of tumours when they grow naturally without the use of
immunotherapy. Although anti-CTLA4 and anti-PD-1 therapies can improve patients' overall
survival with metastatic melanoma, a large proportion of patients also encounter organ-
specific toxicities, also known as immune-related adverse outcomes (IrAEs), which restrict
the long-term advantages of this immunotherapeutic strategy. After TCR-mediated
stimulation, CTLA4, which is primarily expressed on CD4+ T lymphocytes, inhibits
costimulatory CD28 signalling, which lowers TCR-driven proliferation and activation. As a
result, it is thought that suppressing CTLA4 increases CD28 signalling, which reduces the
barrier to anti-tumor T-cell activity and proliferation. An antigen-specific T lymphocyte's
ability to carry out effector functions is impaired when ligand is coupled to the PD-1 cell
surface receptor. Because distinct cell groups that express CTLA-4 are directly affected by
PD-1 blocking, it is expected that PD-1 and PD-1 inhibition exert diverse immunological
processes. It is unclear why T cells cannot limit cancer growth in the absence of
immunotherapies or why certain patients do not respond to CTLA4 or PD-1 inhibition.
Chimeric antigen receptors: Adoptive transfer of autologous T cells produced by genetic
modification to produce receptors recognizing chemicals produced by malignant cells may
have a greater potential to change cancer therapy than TIL- and antibody-based techniques. It
is feasible to introduce genes that make antigen receptors into the patient's T cells. These cells
are then quickly expanded to create memory and effector lymphocytes that have the potential
to multiply rapidly in vivo and exhibit potent anti-tumor activity. One strategy for
overcoming cancer tolerance involves using T cells which have been genetically altered and
modified to produce chimeric antigen receptors (CARs). These synthetic receptors combine
the effector skills of T cells with the ability of antibodies to recognise pre-defined surface
antigens with a high degree of accuracy in a non-MHC limited manner. CARs typically
feature a cytoplasmic tail for tumour antigen identification and one or more intracellular
signalling domains that aid in T-cell activation. The antigen-binding single chain variable
fragment (scFv) element of a CAR is normally created by joining the variable heavy (VH)
and variable light (VL) chains of an antibody by a peptide spacer of around 15 residues in
length. This molecule is coupled to an intracellular signalling molecule that consists of the
TCR CD3 ζ signalling chain (or the intracellular signalling domain of an additional immune
receptor-tyrosine-based-activation-motif [ITAM]-containing protein) and optional tandem co-
stimulation domains such as the 4-1BB or CD28 signalling modules. First generation CARs
just have CD3 ζ whereas second gen chimeric receptors (such 4-1BB/CD3ζ) also have a co-
stimulatory endodomain. Third-generation CARs with numerous co-stimulatory signalling
modules are also being worked on. The fundamental advantage of using CAR-based
approaches for cancer immunotherapy is that the scFv is created from merely an antibody
with preferences that are hundreds of times greater than TCRs.

The identification of malignancies by CAR T cells is neither limited by or dependent on

antigen presentation and processing since scFvs can recognise intact cell surface proteins.
Therefore, MHC-linked tumour escape mechanisms are insensitive to CAR T cells.
Furthermore, antigens such as glycolipids, improperly glycosylated proteins, and structural
epitopes that TCRs find challenging, if not impossible to identify, can be recognised by
CARs. Based on results from clinical trials, there is emerging consensus that CAR T cells
have always displayed the potential to produce significant anti-tumor effects. As a result of
these initiatives, CAR T cells which are targeted against CD19 protein have recently acquired
FDA approval for the treatment of acute lymphoblastic leukaemia and large B-cell lymphoma
(DLBCL).
The full and long-lasting effectiveness of anticancer therapy depends on the formation of an
immune response that is capable of eradicating any tumour cells that may still exist after
chemotherapy or radiation treatment. It will be necessary to employ immunostimulatory
strategies designed to fend off immunosubversion in order to develop an immunogenic
chemotherapy regimen. Some modern chemotherapy regimens may be more effective at
fighting tumours because of their immunostimulatory qualities.