Oncology and Autoimmune Diseases - Different Types of T Cells Contribution

Introduction:

Immune tolerance ensures our immune system avoids attacking the tissues, preserving a delicate balance. Mechanisms, like removing self-reactive cells during development, maintain this equilibrium. Genetic or environmental factors can disrupt this balance, leading to autoimmune diseases. Remarkably, cancer exploits these mechanisms, creating cancer tolerance and evading immune detection. Researchers seek to break this tolerance, enhancing the immune system's ability to combat cancer. Understanding these processes is crucial for effectively advancing strategies to treat autoimmune diseases and cancer.

How Do Different Types of T Cells Contribute to the Complex Interplay Between the Immune System and Cancer?

Understanding T Cells and Cancer:

CD8+ T Cells:

1. These T cells directly attack cancer cells by recognizing specific complexes on their surface.

2. They use perforin and the FAS apoptosis pathway to destroy cancer cells.

Tregs:

1. Regulatory T cells (Tregs) suppress CD8+ T cell function, promoting cancer growth.

2. They also inhibit the proliferation of memory and effector T cells, contributing to cancer progression.

Th1 and Th2 Cytokines:

1. Th1 cytokine IL-2 has anti-tumor activity.

2. Depending on the context, th2 cytokines may have both pro- and anti-tumor effects.

Th17 Cells:

1. Th17 cells' impact on cancer is context-dependent, with pro- or anti-tumor roles.

2. Their levels vary in different cancers and tumor microenvironments.

Involvement of Immune Cells in Cancer:

1. Neutrophils: Dual Nature in Tumors:

1. Tumor-associated neutrophils (TANs) can be pro-inflammatory (N1) or anti-inflammatory (N2) based on TGFβ presence.

2. High-density neutrophils (HDN) exhibit cytotoxicity against cancer cells, while low-density neutrophils (LDN) are innocuous.

2. Macrophages: M1 vs. M2:

1. Macrophages can be pro-inflammatory (M1) or anti-inflammatory (M2).

2. Tumor-associated macrophages (TAMs) may shift from M1 to M2, promoting cancer in later stages.

Role of Reactive Oxygen Species (ROS) in Cancer:

Complex Effects of ROS:

1. ROS are abundant in the tumor microenvironment.

2. ROS influences Tregs function, MHC-I expression, and pathways crucial for tumor growth and metastasis.

Tight ROS Control for Tumor Progression:

1. Optimal ROS levels within the tumor support growth and angiogenesis.

2. Very high or low ROS levels can induce cancer cell death or hinder tumor progression.

Major Histocompatibility Complex (MHC) in Cancer:

MHC-I: Tregs and Immune Evasion:

1. MHC-I expression in Tregs contributes to their suppressive function, aiding cancer progression.

2. TGFβ suppresses MHC-I expression, allowing tumors to evade immune recognition

MHC-II: Vital for Effective Anti-Tumor Immunity:

1. MHC-II expression is important for CD4+ T cell-mediated immune responses against cancer.

2. Tregs can deplete MHC-II from dendritic cells, hindering effective anti-tumor immunity.

Immune Suppression and Cancer Risk:

Immunosuppressive Drugs and Cancer:

1. Non-specific immunosuppressive drugs increase the risk of cancer.

2. Transplant patients using these drugs face a significantly higher cancer risk compared to the general population.

What Is Immune Tolerance and Anti-tumoral Immunity?

Immune Defense Against Cancer:

• Like normal cells, cancer cells activate immune tolerance mechanisms to prevent the immune system from attacking them.

• Central tolerance occurs in bone marrow and thymus organs, where self-reactive immune cells are eliminated during development.

• Even with these mechanisms, some self-reactive cells still exist in the body.

Cancer's Defense Strategies:

• Cancer cells evade the immune response by creating an "immune-privileged" environment.

• Tactics include suppressing immune activity, downregulating immune molecules, and recruiting suppressive cell populations.

• Regulatory cells like Tregs and Myeloid-Derived Suppressor Cells (MDSCs) play a role in inhibiting immune responses.

Importance of Tumor-Infiltrating Cells:

• The immune system can recognize cancer through specific antigens or self-reactive cells.

• Tumor-lysing cells, such as Natural killer (NK) and Cytotoxic T lymphocytes (CTLs), are crucial in combating cancer.

• However, their activity may release self-antigens, potentially triggering autoimmune responses.

Role of Tumor-Infiltrating Lymphocytes (TILs):

• TILs, particularly CD8+ T cells, play a significant role in cancer prognosis.

• High TIL numbers are associated with better disease-free and overall survival.

• Th1 polarization and M1 macrophages contribute to killing cancer cells.

Tumor-Infiltrating B Cells (TIBs):

• The role of TIBs in cancer control is not fully understood.

• They may support T cell function or have suppressive effects through cytokine secretion.

• CD20+ TIBs are generally associated with a good prognosis.

B Cells and Autoimmune Responses in Cancer:

• Autoantibodies are frequently found in cancer patients, both in blood and within tumors.

• Understanding cancer-associated B cell responses and antibody specificity is crucial for early diagnosis and treatment strategies.

What Is the Relationship Between Autoimmune Disease and Cancer?

Autoimmune Diseases and Cancer Risk:

Inflammatory Bowel Diseases (IBD):

• Conditions like ulcerative colitis and Crohn’s disease increase the risk of colorectal cancer.

• Celiac disease is linked to a higher chance of small intestinal cancer.

Inflammation and Cancer:

• Chronic inflammation in the body, caused by factors like infections, chemicals, or obesity-related issues, plays a significant role in the development and progression of cancer.

Autoimmune Diseases Beyond the Gut:

Rheumatoid Arthritis (RA):

• RA, a disorder affecting the immune system, is not strongly associated with an increased risk of cancer.

• However, the use of the anti-cancer drug methotrexate (MTX) for RA treatment can elevate the risk of secondary cancers, particularly lymphoma.

Sjogren Syndrome:

• Primary Sjogren syndrome increases the overall cancer risk, especially for lymphomas like Non-Hodgkin's lymphoma (NHL).

Systemic Lupus Erythematosus (SLE):

• SLE is linked to various cancer risks, including vulva, lung, thyroid, and possibly liver cancers.

• Lymphomas, especially NHL and diffuse large B-cell lymphoma (DLBCL), are commonly associated with SLE.

Systemic Sclerosis, Dermatomyositis, and Polymyositis:

• Systemic sclerosis is implicated in the risk of certain cancers, such as lung and NHL.

• Dermatomyositis and polymyositis increase the risk of nasopharyngeal, lung, and hematopoietic cancers, with the highest risk in the first year after diagnosis, decreasing with age.

Immune Response and Cancer Treatment:

B-Cell and T-Cell Lymphomas:

• Autoimmune diseases are associated with B-cell and T-cell lymphomas, suggesting a connection between chronic inflammation and lymphoma risk.

Immunotherapy and Autoimmunity:

• Studies indicate that immunotherapy for metastatic melanoma triggered autoimmune reactions.

• Tumor shrinkage correlated with signs of autoimmune melanocyte destruction, indicating that the body's immune response can be harnessed for cancer treatment if manageable.

Conclusion:

The intricate relationship between autoimmune responses and cancer involves genetic changes, microbiota factors, and immune imbalances. Specific antibodies (aAbs) from autoimmune reactions can be reliable cancer markers, detectable in small blood samples. Advanced technologies like protein microarrays enable efficient screening for early cancer detection and treatment assessment. Large, standardized studies are essential for comparing results and understanding the clinical applications of aAbs. Examining aAbs in body fluids beyond blood, like cerebrospinal fluid, can expand their use in diagnosing specific cancers. Some autoimmune diseases increase cancer risk, while cancer itself triggers autoimmune responses influenced by tumor proteins and treatment-induced inflammation. Understanding these connections is crucial for optimizing cancer immunotherapy, minimizing adverse events, and maximizing clinical benefits.