June 25, 2024

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How to understand the systemic immunity and therapy of cancer?

How to understand the systemic immunity and therapy of cancer?


How to understand the systemic immunity and therapy of cancer?


The clinical treatment options for tumors are becoming more and more diversified. At present, chemotherapy, surgery and radiotherapy are the mainstays, and various emerging treatment methods such as immunotherapy are flourishing.

Despite some progress , immunotherapy remains ineffective for most cancer patients. More effective and broader immunotherapy requires a deeper understanding of the immunological relationship between tumors and their hosts .


Starting with the peripheral immune system outside the tumor microenvironment (TME) , this article focuses on the reorganization of peripheral immune cells that coincides with malignancy growth , investigates the critical contribution of peripheral immune cells to driving and sustaining effective immunotherapy responses, and The ability of the immune system to coordinate a new immune response upon tumor burden .

Finally, the role of peripheral immune biomarkers in cancer diagnosis and treatment is also discussed .


How to understand the systemic immunity and therapy of cancer?



This review is from the University of California School of Medicine and  different from previous studies in that it takes the peripheral immune system of the tumor microenvironment as an entry point and aims to comprehensively explore the immunotherapy of cancer.



1. Interference of tumor burden on immune tissue

Bone marrow, blood, spleen, and draining lymph nodes (dLNs) form a continuously converging immune network during tumor development.

Studies have shown that disruption of the hematopoietic system is present in many human cancers and mouse cancer models, most prominently in the expansion of peripheral and intratumoral immature immunosuppressive neutrophils in tumor-burdened hosts (usually manifested as accumulation of polymorphonuclear myelin suppressor cells (PMN-MDSCs), monocytes (MMDSCs), and macrophages) .

The expanded cells eventually moved to the TME, resulting in local immunosuppression (Fig. 1a) .


In addition to the overproduction of monocytes and neutrophils , the abnormal presence of dendritic cells is observed outside the tumor of tumor-bearing hosts , which has important implications for the development of antitumor immune responses, as dendritic cells are CD8 + and A key coordinator of CD4 + T cell initiation and differentiation.

In patients with pancreatic or breast cancer and in mouse models of these cancer types, the reduction in the frequency of peripheral conventional dendritic cells (cDC1s) is driven by tumor-derived recombinant human granulocyte colony-stimulating factor (G-CSF) , This resulted in downregulation of IRF8 in dendritic cells, thereby reducing differentiation of mature dendritic cells (Fig. 1a).


Likewise, tumor-derived vascular endothelial growth factor (VEGF) has been shown to inhibit the maturation of dendritic cell precursors.

By increasing the frequency of hematopoietic stem cells (HSCs) and granulocytic progenitors (GMPs) , the bone marrow tends to produce more neutrophils and monocytes. In some cases, this propensity comes at the expense of dendritic cell precursors that share progenitors, leading to a systemic deficiency of dendritic cells .

Another mechanism of dendritic cell deficiency in a mouse model of pancreatic cancer was shown to be mediated by serum IL-6, driving increased dendritic cell apoptosis (Fig. 1b).


Although the causal relationship between cellular receptor (TCR) repertoire diversity and cancer has not been established, studies have shown that breast cancer patients have a reduced ability to produce IL-2 and IFNγ when stimulated with phorbol ester (PMA) and ionomycin , whereas The function of peripheral T cells was also disturbed (Fig. 1b).


As shown in Figure 1c, several changes were observed in the blood of the spleen , including the accumulation of immature neutrophils, monocytes, and semi-mature dendritic cells and decreased abundance of dendritic cells and TCRs.

While the tumor dLN had the most direct association with the tumor, it was characterized by increased frequencies of monocytes and dendritic cells and decreased CD8 + T cells (Fig. 1d).


Collectively, these observations spanning a number of human and mouse tumor models suggest a shift in the peripheral immune milieu to a suppressive state marked by increased anti-inflammatory cells and decreased key mediators of antitumor immunity , further illustrating the systemic nature of immune organization Destruction occurs in different tumor types.

Further research on the different types of immune status in cancer patients and the relationship between these types of immune status and tumor tissue origin, stage of development, and patient demographics is needed in the future in order to provide treatments and interventions to prevent tumor recurrence and metastasis.


How to understand the systemic immunity and therapy of cancer?

Figure 1. Systemic perturbation of immune tissue by tumor burden


2. Systemic responses in immunotherapy

Cancer immunotherapy has fundamentally expanded our ” anti-cancer toolkit “, and in addition to chimeric antigen receptor T cells, bispecific T cell engager (BiTE) therapies and vaccines, the current U.S. Food and Drug Administration (FDA) ) approved 7 immune checkpoint inhibitors (ICIs) covering 19 different cancer types .

The general view among investigators centers on the concept of enhancing cytotoxic effectors within the TME to enhance the efficacy of cancer immunotherapy, and as research progresses, intact peripheral immunity is found to be critical for the efficacy of immunotherapy .

Recent studies have shown that blockade of the PD-1 and PDL-1 axes, including ICI, is dependent on systemic immunity. Furthermore, the microbiome is considered to be a potent immune system modulator .

The activity and composition of the microbiome influences the human immune system, and antibiotic treatment that disrupts the gut microbiome has led to resistance to ICIs in cancer mice and cancer patients.


Antitumor immunotherapies also rely on immune kinetic responses beyond the TME , which process as follows: conventional dendritic cells (cDCs) in the TME uptake tumor antigens and move to draining lymph nodes (dLNs) , followed by direct synapse formation. Transfer antigen to lymph node resident dendritic cells .

Influenced by chronic stimulation and immunosuppressive signals, T cells in the TME reach a state of terminal exhaustion .

Dysfunctional T cells accumulated within tumors and upregulated CD103 and CD38 , consistent with irreversible epigenetic remodeling (Fig. 2a) .


Immune intervention via PD-1 and PDL-1 checkpoint blockade increased the interaction between cDCs and immature T cells in dLN, promoting the initiation and rapid expansion of nascent antigen-specific T cell clones .

Checkpoint blockade also led to the proliferation of existing T-cell clones in the circulation .

These expanded peripheral T cells eventually infiltrated the TME and expressed markers indicative of antigen-specific activation , exhibiting functional cytotoxicity (Fig. 2b) .


How to understand the systemic immunity and therapy of cancer?Figure 2. Systemic Immunotherapy in Cancer Immunotherapy



3. Secondary immune challenge in cancer

Altered cytokine levels, cellular composition, and cellular activation status are known to affect the nature and magnitude of secondary responses in chronic infection and co-infection models.

As systemic immune status is markedly reorganized in tumor-bearing individuals, this may have functional consequences for the coordination of new immune responses.

Identifying systemic functional deficits in cancer patients to immune challenges , such as vaccines or infections, remains challenging due to the impact of common cancer therapies .


Why does the immune status of tumor burden lead to diminished peripheral secondary immune responses? Experiments that do not share antigens with tumors and drive immune responses away from the tumor microenvironment reveal dysfunction in tumor – burdened hosts .

Mice with breast cancer were reported to have a weaker response to immune antibodies and T-cell proliferation, as well as attenuated rejection of allogeneic tumors.

Likewise, our study showed that the spleen of mice infected with L. monocytogenes AT3 mammary tumors had an attenuated antimicrobial response, characterized by decreased expression of dendritic cells CD86, CD80 and CD83 2 days after infection .

Compared with healthy control mice infected with L. monocytogenes, this ultimately resulted in decreased CD8 + T cell proliferation and differentiation 7 days post-infection, which could be rescued by CD40 agonist treatment or surgical removal of the tumor (Fig. 3a). ) .



Mechanistically, some of these challenges (immunity, bacterial infection) are associated with systemic dendritic cell deficiency or impaired activation , as described in the draining lymph node section (Fig. 3b) .

How to understand the systemic immunity and therapy of cancer?Figure 3. Secondary immune challenge in the context of cancer




4. Systemic immune biomarkers in cancer

Despite the interest in developing predictive biomarkers using the systemic immune system, the vast majority of immunotherapy clinical trials are still conducted without the use of biomarkers to guide enrollment.

Currently, while some immunological features in the TME have been shown to correlate with prognosis in a variety of conditions, there are currently not enough defined systemic immune biomarkers to drive this decision.

Therefore, there is an opportunity for immune biomarkers in peripheral blood to help guide patient treatment decisions.


Simple indicators quantified from routine complete blood counts have been shown to correlate with patient outcomes in various human malignancies (see table below for details) .

Among them, the ratio of neutrophils to lymphocytes has become a prognostic indicator in patients with various cancer types.

In addition, in patients with melanoma, non-small cell lung cancer, and renal cell carcinoma, the likelihood of response to ICI immunotherapy was also associated with the ratio of neutrophils to lymphocytes.


Various recent studies have also shown that the proliferation and expansion of CD8 + T cells in peripheral blood is associated with responsiveness to ICI. In melanoma, the ratio of peripheral T-cell proliferation to tumor burden was shown to correlate with responsiveness to anti-PD-1 therapy.

Thus, a recent series of studies have identified the importance of biomarkers captured in peripheral blood analysis for immunotherapy, providing an opportunity for immune monitoring to improve patient care.


Table 1. Approaches to developing predictive biomarkers for cancer therapy




 Conclusion and Outlook

A comprehensive understanding of cancer and host immune responses across different tumor types, patient populations, and therapies requires a detailed understanding of not only the TME, but also macroenvironmental changes in immune tissue. Although many immune tissue alterations have been observed in the peripheral tissues of individuals with tumors, the mechanisms driving many of these features remain unknown .

Therefore, future research is also required to investigate the mechanisms that drive peripheral immune reorganization in order to design therapeutic strategies to restore the disrupted immune system to a healthy homeostatic immune setpoint.

In addition to the reorganization of the immune system in cancer, a growing body of research has also shown that the immune state affected by the tumor does not function in the same way as the undisturbed immune system.

The development of peripherally orchestrated de novo antitumor immune responses is critical for immunotherapy efficacy.


In addition, the study found that surgical resection or blockade of specific cytokines in multiple tumor models restored many peripheral immune perturbations, suggesting that the tumor immune macroenvironment has significant plasticity , and pairing cellular measurements from the tumor and the periphery may be helpful.

To identify and simplify biomarkers that can be easily sampled with blood draws and provide important clinical information to guide treatment.









“Systemic immunity in cancer”https://doi.org/10.1038/s41568-021-00347-z

How to understand the systemic immunity and therapy of cancer?

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