TUMOR IMMUNITY

Group 3
Beenish Razzaq 185019013
Kafilah Zia 18501929
Lucas Zulu 185019009
Maxwell Ahiafor 185019001
Muhammad Kashif 185019017
Nathalyn Campbell 185019026
Q3: Mechanisms by which tumors avoid
immune response.
 Immunosurveillance theory
The immunosurveillance hypothesis states that a physiologic
function of the immune cells is to recognize and destroy
transformed cells
The theory was later appended by Thomas Lewis and Sir
MacFarlane Burnet, who proposed that immunological recognition
of transformed cells was a form of homeostatic surveillance that
could allow the body to guard against malignancies
Implicitly, the hypothesis predicts that the incidence of cancer
would increase or tumor latency periods would be reduced in the
absence of immunosurveillance
Epstein-Barr virus (EBV)-related neoplasms are examples of
cancers usually controlled by immunosurveillance that increase in
incidence in immunosuppressed individuals.
Most Cancers Slip Through the
Immunosurveillance Net
It is important to note that the cancers that immunosuppressed
patients are at an increased risk of developing are not the same as
those that are most commonly found in the general populace.
This implies that most cancers are not covered under the
immunosurveillance theory, and many cancers develop simply
because the immune system does not recognize them as foreign
in the first place.
Cancer cells are basically “altered self-cells” and may not be
very immunologically different from normal cells. In fact, most
cancer cells escape immunosurveillance, because they simply do
not satisfy the primary condition of the immunosurveillance
theory, which requires the distinction of transformed cells from
normal cells.
In principle, tumor development can be controlled by
cytotoxic innate and adaptive immune cells; however,
as the tumor develops from neoplastic tissue to
clinically detectable tumors, cancer cells evolve
different mechanisms that mimic peripheral immune
tolerance in order to avoid tumoricidal attack.
Tumor cells evade the immune attack using two main strategies:
1. avoiding the immune recognition
2. Instigating an immunosuppressive tumor microenvironment
(TME).

 In the first, cancer cells may lose the expression of tumor antigens on the
cell surface, thus avoiding the recognition by cytotoxic T cells. For
example, 40% of non-small cell lung cancers hold a loss of heterozygosity
in human leukocyte antigens (HLAs), which leads to immune escape by
presenting fewer antigens. Notably, HLA loss has been associated with
resistance to T-cell transfer therapy in metastatic colorectal cancer and
poor outcome response to checkpoint blockade immunotherapy in
melanoma and lung cancer patients. In this sense, mutations and deletions
may result in down-regulation of the antigen-presenting machinery and
likely confer resistance to T-cell effector molecules such as TNF-α and
IFN-γ. Additionally, to overcome the attack of NK cells in experimental
metastasis, breast and lung cancer cells down-regulate cell surface NK
activators, becoming invisible to detection by NK cells.
In the second, cancer cell-derived factors instigate an immune-tolerant
TME by
1. secretion of suppressive molecules such as IL-10, TGF-β,
prostaglandin E2, and VEGF
2. expression of inhibitory checkpoint molecules such as PD-L1,
CTLA-4, and V domain immunoglobulin suppressor of T-cell
activation (VISTA); and
3. induction of the recruitment of TAMs, MDSCs, and Tregs by tumor-
derived chemokines such as CCL2, CSF1, CCL5, CCL22, CXCL5,
CXCL8, and CXCL12.
Combined, these strategies result in a complex and efficient system for
immune evasion. Therefore, multimodal therapies aimed at disrupting
different aspects of the immune-tolerant apparatus in cancer may
improve the efficiency of current immunotherapies. In this regard, two
studies showed recently that the TGF-β blocking increases the
therapeutic response of anti-PD-L1 therapy, resulting in tumor
regression in EMT6 breast carcinoma models and complete elimination
of established liver metastases from a colorectal cancer model.
 EVADING THE CTLS
Tumor cells often have an altered expression pattern of class I
molecules, as a consequence of profound defects in the antigen
processing pathway. This promotes poor expression or loss of
class I peptide presentation, which permits tumor cell escape
from CTL killing.
Production of immunosuppressive molecules that downregulate
the expression of MHC class I on nucleated cells and defects in
the antigen processing machinery have been clearly
demonstrated by examining tissue samples from several cancers.
Recently, by microdissection and reverse transcription-
polymerase chain reaction, a problem in the presentation of class
I peptide was detected in transformed colon cells
 TRICKING THE NK CELLS
In order to escape NK-mediated killing, cancer cells have
evolved to establish tolerance using similar mechanisms as
those found in fetal–maternal interactions. HLA-G is a
nonclassical MHC class I molecule expressed in the placenta
and helps to maintain tolerance to the fetus. It is expressed by
many cancers like melanoma, renal carcinoma, lung
carcinoma, glioblastoma, and ovarian cancer. It is up regulated
through the local expression of environmental factors such as
cytokines, stress factors, and chemotherapeutic agents. HLA-
G exerts its immunoinhibitory effects through at least three
KIRs expressed by nearly all cells of the immune system, and
therefore has powerful immunosuppressive effects.
THANK YOU