Autoimmunity in Cancer: Mechanisms Implications and the Role in Tumor Immunotherapy

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Autoimmunity in Cancer: Mechanisms Implications and the Role in Tumor Immunotherapy

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Autoimmunity in Cancer: Mechanisms Implications and the Role in Tumor Immunotherapy

Over the last decade, tumor immunotherapy, which harnesses the immune system to fight cancer cells, has become a dominant force in cancer treatment.

One of the key approaches is using immune checkpoint inhibitors (ICI) to unleash the immune system’s full potential, enabling immune cells to attack cancerous cells.

ICIs have demonstrated significant clinical benefits in various types of solid tumors, such as renal cell carcinoma and advanced melanoma.

However, these therapies, including ICIs and cytokines, can nonspecifically stimulate the immune system, potentially activating self-reactive lymphocytes.

This may lead to immune-related adverse events (IRAEs), such as skin damage, colitis, and thyroiditis, limiting the clinical efficacy of these treatments.

Understanding the characteristics and mechanisms of autoimmune responses observed in solid tumors is crucial.

It can shed light on the mechanisms of immune tolerance, helping to optimize immunotherapy approaches to minimize immune-related toxicity.

Additionally, it could lead to the discovery of urgently needed tumor biomarkers for early diagnosis and precise prognosis.

Immune Tolerance and Anti-Tumor Immunity

To survive, cancer cells must evade immune detection, a process known as immune escape, which is considered a hallmark of cancer. Tumor cells employ several strategies to create an “immune tolerance privilege,” including expressing immunosuppressive cytokines, downregulating major histocompatibility complex (MHC) molecules, inducing lymphocyte apoptosis through molecules like PD-L1, preventing T-cell activation, and recruiting immunosuppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to inhibit the infiltration of effector lymphocytes.

In tumor immunotherapy, the immune system can recognize cancer cells through tumor-associated antigens (TAAs) or self-reactive lymphocytes. This blurs the boundary between autoimmunity and anti-tumor immunity, as immune tolerance may be compromised during an anti-tumor response. The key players in overcoming the immunosuppressive tumor microenvironment (TME) are components of cellular immunity, such as natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTLs). While these cells are effective in lysing tumor cells, they may also trigger autoimmune reactions.

Compared to T cells, much less is known about tumor-infiltrating B cells (TIBs). TIBs can enhance T effector functions through cytokine production or antigen presentation. They also act as opsonins, activating the complement pathway or inducing antibody-dependent cellular cytotoxicity (ADCC). However, TIBs can also suppress T-cell responses by recruiting Tregs or secreting immunosuppressive cytokines like IL-10 or TGF-β.

Autoimmune responses related to B cells often appear in the sera of patients with solid tumors. One study reported that 84% of breast cancer tissues contained autoantibodies secreted by TIBs. Understanding the cancer-associated B-cell response and the antigen specificity of autoantibodies (AABs) is essential, as antibodies are stable and easy to detect. This could aid in early diagnosis, treatment selection, and prognosis, as well as guide the development of new tumor immunotherapies.

Origins of Autoimmune Responses in Tumors

The triggers for autoimmune responses in cancer may be multifactorial, including host genetic factors, the inflammatory environment, the nature of TAAs, and the effects of cancer treatment interventions.

1. Shared Genetic Factors: Both cancer and autoimmune diseases involve genetic alterations, such as gene mutations or single nucleotide polymorphisms (SNPs), affecting key proteins involved in both cancer and autoimmunity. For instance, mutations in the pro-apoptotic gene TP53, common in many solid tumors, have been shown to increase autoimmune susceptibility in animal models.

2. Microbiome: The microbiome, especially the gut microbiota, serves as a physical and biochemical barrier for the immune system, shaping immune responses. Disruptions in the gut microbiota have been linked to diseases like Crohn’s disease, rheumatoid arthritis, and respiratory disorders. Additionally, the gut microbiome plays a significant role in forming tumor immune responses. Antibiotic-induced dysbiosis, for example, can reduce the efficacy of ICI treatment in renal cell carcinoma, highlighting the microbiome’s role in therapy response.

3. Tumor Immunotherapy: ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have achieved significant success in cancer treatment. However, ICI-induced autoimmune reactions can occur when the blockade of immune checkpoints results in the activation of self-reactive T cells, leading to IRAEs.

4. Conventional Tumor Therapies: Chemotherapy, in addition to immunotherapy, may also trigger autoimmune responses. Chemotherapy often induces widespread apoptosis, releasing autoantigens that may create an immunogenic environment.

5. Altered Autoantigens: Tumor-related autoantibodies may target mutated or truncated autoantigens or proteins with abnormal post-translational modifications (PTMs).

Significance of Autoimmune Responses in Solid Tumors

• Autoantibodies (AABs):
  Autoantibodies can sometimes be detected months before the onset of cancer, making them promising tools for early cancer detection. They also have potential prognostic value, as certain AABs have been associated with longer survival in cancer patients.

• Immune-Related Adverse Events (IRAEs):
  While IRAEs may limit the clinical application of ICIs, in some cases, their occurrence is associated with favorable treatment outcomes. For instance, vitiligo in melanoma patients treated with ICIs has been linked to better survival.

Conclusion

Autoimmune responses in the tumor environment and during immunotherapy are complex, driven by genetic changes, microbiome factors, and immune imbalances. Autoantibodies offer promise as biomarkers for early cancer diagnosis and prognosis, and understanding these responses is crucial for improving cancer immunotherapy while minimizing IRAEs. Further research will enhance the clinical benefits of immunotherapy, ensuring effective anti-tumor responses with minimal toxicity.

Autoimmunity in Cancer: Mechanisms Implications and the Role in Tumor Immunotherapy

Reference:

1.Autoimmune Responses inOncology: Causes and Significance. Int J Mol Sci. 2021 Aug; 22(15): 8030.

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.