Systemic immune landscape of cancer

preface

Cancer is a systemic disease, and long-term inflammation is one of the main hallmarks of
cancer.
Whether this inflammation triggers tumorigenesis or supports tumor growth depends on the environment, but ultimately the systemic immune landscape beyond the tumor changes significantly during tumor progression
.

The field of tumor immunology focuses on local immune responses in the tumor microenvironment (TME), whereas immunity is coordinated across tissues
.
Without continuous communication with the periphery, a local anti-tumor immune response cannot be present
.
In addition, almost every subset of immune cells is involved
in cancer biology.
Therefore, a thorough understanding of the cancer immune response must include the entire peripheral immune system as well as all immune cell lineages
within TME.

Perturbations caused by tumor burden

Many human and mouse cancer models lead to widespread disruption
of hematopoietic function.
This disruption is most pronounced by the expansion of immature neutrophils and monocytes in the periphery of the tumor host, which then enter TME and lead to local immunosuppression
.

Hematopoietic stem cells and progenitor cells are mobilized into the proliferation and differentiation of monocytes and granulocyte lines, resulting in peripheral expansion and intratumor accumulation of immature immunosuppressive neutrophils, including polymorphonuclear myelo-derived suppressor cells (PMN-MDSCs), monocytes (M-MDSCs), and macrophages
。 A comprehensive meta-analysis of more than 40,000 patients found that elevated neutrophil frequency in the blood, as measured by neutrophil-to-lymphocyte ratio, was associated with poor outcomes in patients with mesothelioma, pancreatic, renal cell carcinoma, colorectal cancer, gastroesophageal cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, and hepatocellular carcinoma.

In addition to the overproduction of monocytes and neutrophils by abnormal hematopoiesis, dendritic cell perturbations
are observed on the periphery of the tumor-burdening host.
This has important implications for the development of anti-tumor immune responses, as dendritic cells are in many cases key coordinators
for the initiation, differentiation and proliferation of CD8+ and CD4+ T cells.
Cancer patients have fewer
DC cells in their peripheral blood compared to healthy controls.

The perturbation of T cells in the most studied cancer is the expansion of peripheral inhibitory CD4+ regulatory T (Treg) cells and their invasion into the tumor
.
Recent studies have shown that Treg cells in the blood of cancer patients have the same phenotype and TCR profile as intratumor T cells, suggesting that a significant proportion of intratumor suppressor Treg cells are derived from naturally occurring thymic Treg cells rather than differentiated by tumor-induced naïve CD4+ T cells
.

Another suppressor lymphocytes that play a role in tumor progression are regulatory B cells, which are characterized by the production of the anti-inflammatory cytokine IL-10
.
Similar to Treg cells, expansion of regulatory B cells is observed in the peripheral blood of patients with gastric and lung cancer, while the frequency of total B cells remains unchanged
.

In addition, natural killer (NK) cells are another important component of
anti-tumor immunity.
Peripheral NK cells in breast cancer patients also have an altered phenotype characterized by decreased expression of activating receptors, including NKp30, NKG2D, DNAM-1, and CD16, and in patients with gastrointestinal stromal tumors, peripheral NK cells show reduced expression levels of the activation receptor NKp30, and degranulation is impaired
after NKp30 crosslinking.

Changes in the immune system caused by traditional treatments

Traditional treatment strategies for cancer, including chemotherapy, radiation and surgery, can also disrupt the immune landscape
throughout the body.
Understanding these systemic immune consequences is important
for designing strategies that enhance, rather than hinder, the anti-tumor immune response.

Chemotherapy and radiotherapy

Chemotherapy and radiation therapy aim to target cancer cells
by disrupting cell integrity during division.
However, these drugs can also induce immune remodeling that hinders or enhances the overall therapeutic effect
.

The effects of chemotherapy and radiation on the immune system largely depend on the environment
.
In non-small cell lung cancer, standard, prolonged low-dose radiation therapy results in myeloid cell expansion, reduced antigen-presenting cell function, and impaired
T cell response.
Similar immune effects
were observed in cervical cancer patients after combination chemotherapy and radiotherapy.

Chemotherapy can enhance systemic anti-tumor immunity while disrupting cancer cell division
.
Recent studies have shown that an effective response to preoperative neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) induces the recruitment of new T cell clones to TME rather than the expansion of original cells
.
In addition, different breast cancer subtypes exhibit different immune responses to chemotherapy, reflected in the
function of peripheral CD8+ T cells.
Patients with estrogen receptor-positive (ER+) breast tumors had decreased function of circulating PD1+CD8+ T cells, while patients with ER+HER2+ breast tumors had complete loss of function
in this subgroup.
In contrast, patients with TNBC exhibit elevated high-functioning PD1+CD8+ T cells, producing effector cytokines, including IFN-γ, TNF, and granzyme B, with evidence of
clonal amplification.

Tumor removal

Several recent studies have shown that systemic wound healing induces myeloid immune cell remodeling
.
Resection of wounds that do not depend on the removal of the primary tumor can trigger healing, improve circulating IL-6, G-CSF, and CCL2, and ultimately push myeloid subsets into immunosuppressive states
.

However, there is evidence that primary tumors may be a major driver of systemic immune
remodeling.
Successful excision of the primary tumor in mouse models of breast and colon cancer is sufficient to restore normal systemic immune tissue to a large extent, making immune cells comparable
to that of healthy control mice.

Therefore, surgery can have harmful and beneficial effects on
the systemic immune system.
Immunosuppressive mechanisms triggered by early postoperative wound healing may provide a window
of opportunity for cancer cell growth.
However, a reduction in the burden of primary tumors can eventually restore systemic immunity, resulting in a strong adaptive response
.
It will be important
to discover how cancer type, especially disease stage, affects immune reconstitution after surgery and the resulting metastatic potential.

Systemic responses in immunotherapy

The dominant view of the effectiveness of cancer immunotherapy revolves around the concept of revitalizing cytotoxic effectors within TME, but the fundamental systemic understanding of effective anti-tumor immunity is growing
in this field.
Recent studies have shown that immune checkpoint inhibitors (ICIs) rely on systemic immune mechanisms to achieve potent anti-tumor responses
.
In addition, the microbiome is becoming an effective regulator of the immune system
.

Complete peripheral immunity is essential for immunotherapy effectiveness

Complete peripheral immune function, communication, and transport are necessary for
ICI to be effective.
Systemic chemotherapy may disrupt peripheral immune integrity, thereby hindering the therapeutic effect of PD-1 blockade, leading to systemic lymphatic depletion and eliminating long-term immune memory
.
In contrast, local chemotherapy avoids damaging peripheral immunity and, in synergy with PD-1 blockade, induces dendritic cell infiltration into tumors and clonal expansion of antigen-specific effector T cells
.

CD103+ dendritic cells migrate from tumors to dLN via a CCR7-dependent mechanism to transport tumor antigens to the peripheral immune system, and these dendritic cells can then also excite tumor-specific T cells
.
Newly started tumor-specific T cells then flow from lymph nodes to tumors, and this cycle is an important process
in natural and therapeutically induced anti-tumor immunity.

Effective immunotherapy drives a new immune response

The antitumor response ultimately requires functional effector lymphocytes within TME to mediate cancer cell
killing.
However, over time, intratumor T cells may become depleted, preventing them from performing key effector functions
.

To overcome local immune dysfunction, effective immunotherapy drives a new peripheral immune response, ultimately leading to new effector T cell infiltration
.
Some reports have now shown that PD-1 and PD-L1 blockade can drive new T cell clones into TME that did not exist
prior to treatment.
In addition, anti-CTLA-4 has also been shown to significantly increase peripheral T cell responsiveness in melanoma patients, suggesting that novel T cell priming is a mechanism of
action.

Together, these results support the idea that not only is peripheral immunity involved in the novel antitumor response, but that de novo initiation of additional naïve T cells with neoantigen specificity also contributes to effective immunotherapy
.

brief summary

In addition to the restructuring of the immune system in cancer, there is growing evidence that the immune state of tumor burden differs
from the function of the immune system that is not disturbed.
The development of a peripherally coordinated de novo anti-tumor immune response is critical
for immunotherapy effectiveness.
Any functional abnormalities in the tumor's immune system can lead to poor immunotherapy
.
Therefore, it is necessary for us to conduct more in-depth research on the global system immunity in cancer, which will help us develop tumor immune drugs and discover
new targets.

References:

1.
Systemic immunity in cancer.
Nat Rev Cancer.
2021; 21(6): 345–359.

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