What is the role of Immune System in Cancer treatment?

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What is the role of Immune System in Cancer treatment?

Cancer is a systemic disease, with chronic inflammation being one of its primary hallmarks.

Whether this inflammation triggers tumor initiation or supports tumor growth depends on the environment, but ultimately, during the progression of the tumor, there are significant changes in the systemic immune landscape outside the tumor itself.

The field of tumor immunology primarily focuses on local immune responses within the tumor microenvironment (TME).

However, immunity is coordinated across tissues, and without continuous communication with the periphery, local anti-tumor immune responses cannot exist.

Furthermore, nearly every immune cell subset is associated with cancer biology.

Therefore, a comprehensive understanding of immune responses in cancer must encompass the entire peripheral immune system as well as all immune cell lineages within the TME.

Disturbances Induced by Tumor Burden

Many human cancers and mouse cancer models lead to widespread disruption of hematopoiesis.

This disruption is most notably manifested by the expansion of immature neutrophils and monocytes in the host’s periphery, which then enter the TME and contribute to local immune suppression.

Hematopoietic stem and progenitor cells are mobilized into the proliferation and differentiation of monocytes and granulocytes, leading to the peripheral expansion and intratumoral accumulation of immature immunosuppressive neutrophils, including polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), monocytes (M-MDSCs), and macrophages. A comprehensive meta-analysis of over 40,000 patients found an elevated frequency of neutrophils in the blood, as determined by the neutrophil-to-lymphocyte ratio, associated with poor prognosis in patients with mesothelioma, pancreatic cancer, renal cell carcinoma, colorectal cancer, gastroesophageal cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, and hepatocellular carcinoma.

In addition to the excessive production of monocytes and neutrophils through aberrant hematopoiesis in response to tumor burden, disturbances in dendritic cells (DCs) have been observed in the periphery of tumor-bearing hosts. This has critical implications for the development of anti-tumor immune responses, as DCs often serve as key coordinators of CD8+ and CD4+ T cell activation, differentiation, and proliferation in many contexts. Peripheral blood DC counts are reduced in cancer patients compared to healthy controls.

One of the disturbances in T cells studied extensively in cancer is the expansion of peripheral suppressive CD4+ regulatory T (Treg) cells and their infiltration into tumors. Recent research suggests that Treg cells in the blood of cancer patients share the same phenotype and TCR repertoire as T cells within the tumor, implying that a significant portion of intratumoral inhibitory Treg cells originates from naturally occurring thymic Treg cells, rather than differentiating from naïve CD4+ T cells induced by the tumor.

Another inhibitory lymphocyte playing a role in tumor progression is regulatory B cells, characterized by their production of the anti-inflammatory cytokine IL-10. Similar to Treg cells, an expansion of regulatory B cells has been observed in the peripheral blood of gastric and lung cancer patients, while the overall B cell frequency remains unchanged.

Furthermore, natural killer (NK) cells are another important component of anti-tumor immunity. Peripheral NK cells in breast cancer patients exhibit altered phenotypes, characterized by reduced expression of activating receptors including NKp30, NKG2D, DNAM-1, and CD16. In gastrointestinal stromal tumor patients, peripheral NK cells show reduced expression levels of the activating receptor NKp30, and degranulation is impaired following NKp30 cross-linking.

Changes in the Immune System Induced by Conventional Treatments

Traditional treatment strategies for cancer, including chemotherapy, radiation therapy, and surgery, also disrupt the systemic immune landscape. Understanding these systemic immune consequences is crucial for designing strategies that enhance rather than inhibit anti-tumor immune responses.

Chemotherapy and Radiation Therapy

Chemotherapy and radiation therapy are aimed at targeting cancer cells by disrupting cell integrity during cell division. However, these treatments can also induce immune remodeling, either hindering or enhancing overall therapeutic efficacy.

The impact of chemotherapy and radiation therapy on the immune system largely depends on the context. In non-small cell lung cancer, standard prolonged low-dose radiation therapy leads to the expansion of myeloid lineage cells, reduced antigen-presenting cell function, and impaired T cell responses. Similar immune effects have been observed in cervical cancer patients following combined chemotherapy and radiation therapy.

Chemotherapy can enhance systemic anti-tumor immunity while simultaneously disrupting cancer cell division. Recent research indicates that effective responses to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) induce recruitment of new T cell clones into the TME that did not exist prior to treatment. Additionally, different breast cancer subtypes exhibit distinct immune responses to chemotherapy, reflected in the functionality of peripheral CD8+ T cells. Estrogen receptor-positive (ER+) breast tumor patients show decreased functionality of PD1+CD8+ T cells in circulation, with ER+HER2+ breast tumor patients exhibiting complete loss of function within this subset. Conversely, TNBC patients display elevated functionality of PD1+CD8+ T cells, producing effector cytokines including IFN-γ, TNF, and granzyme B, with evidence of clonal expansion.

Tumor Resection

Recent studies suggest that systemic immune cell reshaping is induced by systemic wound healing in response to trauma, not necessarily dependent on primary tumor resection. Trauma from either resection or non-resection origins can trigger healing, elevating circulating levels of IL-6, G-CSF, and CCL2, ultimately pushing myeloid subpopulations towards an immunosuppressive state.

However, evidence also suggests that the primary tumor may be a major driver of systemic immune remodeling. Successful removal of the primary tumor in mouse models of breast and colon cancer is sufficient to largely restore normal systemic immune tissue, aligning immune cell populations with those of healthy controls.

Therefore, surgery can have both detrimental and beneficial effects on the systemic immune system. Early postoperative wound healing-induced immunosuppressive mechanisms may provide a window of opportunity for cancer cell growth. However, the reduction of the primary tumor burden can ultimately restore systemic immune competence, leading to a strong adaptive response. Understanding how cancer type, especially the disease stage, influences postoperative immune reconstitution and the potential for metastasis will be of utmost importance.

Systemic Responses in Immunotherapy

The mainstream view of the effectiveness of cancer immunotherapy revolves around reinvigorating cytotoxic effector cells within the TME.

However, the field is increasingly recognizing the fundamental systemic understanding of effective anti-tumor immunity.

Recent research indicates that immune checkpoint inhibitors (ICIs) rely on systemic immune mechanisms to achieve effective anti-tumor responses.

Furthermore, the microbiome is emerging as an effective modulator of the immune system.

Complete peripheral immunity is crucial for the effectiveness of immunotherapy

Intact peripheral immune function, communication, and transport are essential for the efficacy of immune checkpoint inhibitors (ICIs). Systemic chemotherapy may disrupt peripheral immune integrity, impeding the therapeutic effects of PD-1 blockade, resulting in systemic lymphodepletion and the elimination of long-term immune memory. In contrast, localized chemotherapy can avoid harming peripheral immunity, synergizing with PD-1 blockade to induce dendritic cell infiltration into tumors and clonal expansion of antigen-specific effector T cells.

CD103+ dendritic cells transport tumor antigens to the peripheral immune system from the tumor to draining lymph nodes via a CCR7-dependent mechanism. These dendritic cells can subsequently activate tumor-specific T cells. The newly primed tumor-specific T cells then traffic from lymph nodes to the tumor, and this circulation is a critical process in both natural and therapy-induced anti-tumor immunity.

Effective immunotherapy drives new immune responses

Anti-tumor responses ultimately require functional effector lymphocytes within the tumor microenvironment (TME) to mediate cancer cell killing. However, over time, T cells within the tumor may become exhausted, rendering them unable to perform key effector functions.

To overcome local immune dysfunction, effective immunotherapy drives new peripheral immune responses, ultimately leading to the infiltration of new effector T cells. Some reports now indicate that PD-1 and PD-L1 blockade can drive the clonal expansion of new T cells into the TME that did not exist prior to treatment. Furthermore, anti-CTLA-4 has been shown to significantly increase peripheral T cell reactivity in melanoma patients, suggesting a mechanism of action involving the initiation of new T cells.

In summary, these findings support the notion that not only does peripheral immunity play a role in new anti-tumor responses, but also the initiation of additional naïve T cells with novel antigen specificity contributes to effective immunotherapy.

Conclusion

In addition to the immune system’s reprogramming within cancer, mounting evidence suggests that the immune status of the tumor burden differs from that of an undisturbed immune system.

The development of a coordinated peripheral de novo anti-tumor immune response is critical for the effectiveness of immunotherapy.

Any abnormalities in immune function within the tumor microenvironment can potentially lead to suboptimal immunotherapy outcomes.

Therefore, it is imperative that we delve deeper into the systemic immune landscape in cancer to aid in the development of tumor immunotherapeutics and the discovery of new targets.