MANUSCRIPT
The innate and adaptive immune responses are critical for the
recognition and removal of pathogens. Moreover, in the last two decades
it has been demonstrated that immune cells are also key cells in the
cancer-related immune response.1 Ideally, the immune
system should eradicate the tumor cells to maintain homeostasis.
However, it has been demonstrated that a dysregulation of the innate and
adaptive immune responses could lead to tumorigenesis, inhibition of T-
and B-cell activation, and stimulation of tumor proliferation and
metastasis.2 The immune system can also promote tumor
progression through a dynamic process called cancer immunoediting, by
which cancer cells acquire mutations that allow them to evade the immune
system. Tumor cells that undergo this process harbour a reduced
immunogenicity and produce regulatory cytokines such as interleukin-10
(IL-10) and transforming growth factor β (TGF- β) that can inhibit
T-cell functionality.2
The role of T cells in tumor immunity has been extensively studied.
Several subsets of CD4+ T helper (Th) cells are involved in tumor
immunity, but the main ones are Th1 and Th2. Each type produces a
different set of cytokines and present divergent outcomes in cancer
immunity. Th1 responses are frequently described as antitumoral because
they contribute to the activation of cytotoxic CD8 T cells and
macrophages, which has been linked to tumor regression. However, the
role of Th2 immunity in cancer is controversial. Th2 cells produce
pro-inflammatory cytokines such as IL-4, IL-5 and IL-13, leading to
inflammation, which can promote tumor progression. On the other hand,
the same Th2-related cytokines can exhibit antitumoral activity through
eosinophil recruitment in the tumor environment.3 Th1
and Th2 immunity can be regulated by multiple mechanisms. As
aforementioned, the pleitropic cytokine TGF-β is able to inhibit immune
responses by blocking Th1 and Th2 effector cell activity. In the tumor
environment, the re-activation of cytotoxic T-cell responses via TGF-β
inhibition has been proposed as an approach for cancer immunotherapy
(IT).
Cancer IT, described as a type of therapy that reduces tumor burden by
inducing or suppressing the immune system, has become a pivotal strategy
for cancer IT. It usually follows two different strategies. The first is
the inhibition of immune checkpoints responsible to induce tolerance,
which empowers the natural function of the immune system. In this
context, the inhibitors targeting cytotoxic T lymphocyte-associated
protein 4 (CTLA-4) and programmed cell death protein 1/programmed cell
death ligand 1 (PD-1/PD-L1) have emerged as the gold standard of care
regimens for patients with different cancer types.4The second approach involves T-cell engineering to express chimeric
antigen receptors (CAR-T) that specifically detect the cancer cell.
Considering their use and therapy in a broad spectrum of cancer types,
they constitute a potent new cancer therapy.5
The recent article by Liu et al . investigated type 2 immune
responses and a cancer immune tolerance mechanism mediated by
TGF-β.6 They used a mouse model of metastatic breast
cancer and depleted TGF-β receptor 2 (TGFR2) in lymphocytes. When TGF-β
signalling was inhibited in CD4+ lymphocytes, the tumor tissue underwent
remodelling: the vasculature became less leaky and large tumor regions
remained avascular, thus creating a hypoxic region where cells undergo
apoptosis. These changes appeared to be mediated through the hallmark
Th2 cytokine IL-4, and the authors showed an IL-4-dependent gene
signature that correlates to survival in other cancer types
(Figure 1 ).7
In this regard, the IL-4 axis is drawing an increasing interest as a
target for pathologies with an immune underlying mechanism. The blockade
of the IL-4Rα (the receptor for of IL-4 and IL-13) with monoclonal
antibodies such as dupilumab has emerged as a promising strategy for the
treatment of certain allergic diseases such as atopic dermatitis and
allergic asthma.8 Given the findings from Liu et
al ., where IL-4 acts as the downstream mediator of TGF-β pro-tumor
effects, cancer patients may benefit from IL-4Rα blockade.
Liu et al . found IL-4 effects to be mediated through blood vessel
remodelling: when TGF- β siglaning is specifically blocked in CD4+
lymphocytes, it occurs a rearrangement of the vasculature that leaves
large tumor areas without irrigation. Consequently, they experience
hypoxia and prone to cell death.
Regardless of the potential of the discovery, hypoxia signalling has
been studied to influence the first steps of the metastatic process.
Hypoxia has been shown to promote Epithelial-to-mesenchymal transition
(EMT) 6 but also to mediate resistance mechanisms in
anticancer therapy 9 and to shape certain circulating
tumor cells to become highly metastatic.10 Ye and
collaborators 9 established a panel of genes to
monitor the effects of tumor hypoxia on treatment sensitivity and
resistance, including IT. On this subject, a personalized approach may
be needed.
The discovery that TGFR2 deletion in CD4+ cells leads to tumor cell
death in a metastatic breast cancer animal model through vasculature
remodelling opens new interesting therapeutic lines. Nonetheless, the
possible resistance mechanisms due to the ambiguity of hypoxia effects
remain to be elucidated.
Altogether, these discoveries demonstrate the importance of personalized
medicine for the design of potential therapeutic strategies in cancer.
Novel IT strategies including hypoxia-mediated therapy
response-sensitivity may potentiate CD4+ T-cell effects by altering the
TGF-β pathway, thus improving cancer patients prognosis.
Figure 1 : In a breast cancer animal model, Liu et al found that
TGF-β signalling on CD4+ cells contributed to tumor growth and
neoangiogenesis. When the signalling was turned off specifically in Th2
cells, large tumor areas remained hypoxic due to the lack of
vasculature, and prone to undergo cell death. These effects were
mediated through effector cytokine IL-4.