Introduction
Immunotherapy has demonstrated significant and long-lasting therapeutic responses, offering a breakthrough treatment for several forms of resistant carcinoma that progressively alters the tumor's sensitivity to treatment.
The majority of patients either do not react to immunotherapy or eventually gain resistance to treatment after receiving it for a while. Tumor immune resistance pathways are complex, encompassing gene expression, metabolism, inflammation, aberrant neovascularization, and other factors. Several immunotherapy resistance mechanisms are currently being investigated, and more are still being uncovered to increase immunotherapy's effectiveness and broaden its therapeutic uses.
Cancer immunotherapy resistance arises from tumor-intrinsic (signaling pathway alterations, immune response changes) and tumor-extrinsic factors (host-related factors, local tumor microenvironment).
What Is the Role of Tumor-Intrinsic Factors in Immunotherapy Resistance?
When the immune system fights tumors, it involves processes like presenting tumor-related signals to T cells, which are key for eliminating cancer cells. Antigen-presenting cells (APCs) play a crucial role, including specialized cells like dendritic cells, monocyte-macrophages, and others. Changes in these processes can lead to resistance to immunotherapy.
One crucial aspect is the expression of tumor antigens and alterations in their ability to trigger immune responses. High tumor mutation burden (TMB), microsatellite instability, and mismatch repair deficiency (dMMR) are features linked to strong immune responses and positive reactions to immune checkpoint inhibitors (ICIs). These features lead to the formation of new antigens (neoantigens), making tumors more visible to the immune system. However, tumors can counteract this by reducing or losing antigen expression, using mechanisms like antigen shedding, and even changing the antigens themselves.
Sometimes, tumors can adapt by a process called "antigenic drift," similar to viruses, causing mutations in the antigens that help them escape the immune system's attack. The immunogenicity of cell death in tumors, determined by processes like endoplasmic reticulum (ER) stress and autophagy, is essential. Active autophagy machinery and proper responses to ER stress make tumors more susceptible to immune cells. Conversely, resistance can occur if tumors do not respond well to these processes.
Mitochondrial metabolism also plays a role in affecting the presentation of antigens. In patients responding well to treatments, there were high concentrations of proteins related to mitochondrial metabolism and antigen presentation. However, inhibiting mitochondrial energy metabolism hindered the antigen presentation process, leading to resistance.
What Is the Role of Antigen Presentation Pathway and Signaling Alterations in Immunotherapy Resistance?
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Antigen Presentation Pathway Changes: In the immune system's fight against tumors, there is a crucial process where signals from tumors are presented to T cells, activating them to attack. However, alterations in this process, particularly in the antigen presentation pathway, can make T cells ineffective and allow tumors to escape the immune response. Changes in the structural makeup of major histocompatibility complex (MHC) molecules, caused by gene mutations or epigenetic changes, can impact the presentation of tumor-related signals. For instance, mutations in genes like β2-microglobulin can impair the proper expression of MHC molecules on the cell surface, hindering the immune response. In some cancers, tumors use a strategy called immune escape by overexpressing non-classical MHC-I molecules, preventing the immune system from recognizing and attacking them.
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Signaling Pathway Alterations: Interferon γ (IFN-γ) is a crucial cytokine produced by immune cells. It activates pathways that regulate the immune response, including increasing the expression of molecules like Programmed Cell Death Ligand I (PD-L I) on tumor cells. It also recruits immune cells to fight tumors and directly inhibits tumor cell growth. However, in patients receiving immunotherapy, tumor cells can alter or downregulate the signaling pathways influenced by IFN-γ, leading to resistance.
What Is the Role of Tumor-Cell Involvement in Immunotherapy Resistance?
- Secretion of Inhibitory Molecules: Tumor cells resist immunotherapy by releasing substances that hinder the immune response. Exosomes, tiny particles released by cells, carry inhibitory molecules like PD-L I. These molecules suppress the activity of various immune cells outside the tumor microenvironment (TME), promoting immune escape. Some experiments showed that interfering with a protein called Huntingtin-interacting protein I-related protein could change the expression of PD-L I, affecting the cytotoxicity mediated by T cells.
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Genetic Mutations and Signaling Pathways: Functional mutations in genes of tumor cells contribute to immunotherapy resistance. The wingless-related integration site (Wnt/β-catenin) signaling pathway, when abnormal, prevents the infiltration of immune cells into the TME. Enhanced mitogen-activated protein kinase signaling, another pathway, can hinder the function of tumor-infiltrating lymphocytes and promote the recruitment of regulatory T cells (Tregs), leading to immune escape. Loss of tumor suppressors like phosphatase and TENs in homolog deleted on chromosome 10 and oncogenic cyclin-dependent kinases IV and VI signaling are also linked to an immunosuppressive microenvironment and resistance to therapy.
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Gene Mutations and Immunotherapy Response: Different gene mutations in tumors impact responses to immunotherapy. For instance, tumors with epidermal growth factor receptor mutations may be less responsive, while cancer in Kirsten rat Sarcoma virus mutations can enhance the benefits of immunotherapy. Studies also show that specific mutations, like in serine/threonine kinase 11, can lead to resistance in certain cancers.
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Tumor Metabolism Impact: Tumor cells change their metabolism to resist the immune system. Altered metabolism creates a hypoxic, acidic environment that inhibits immune cell function. Additionally, the depletion of tryptophan, a key amino acid for T cell activation, and the production of adenosine contribute to immune suppression. Cholesterol metabolism in tumor cells can also modulate the immune response.
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Microenvironment Factors: The local tumor microenvironment plays a crucial role in immunotherapy resistance. Immunosuppressive cells like regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) inhibit immune responses. Abnormal neovascularization, triggered by proangiogenic factors, further obstructs immune cell entry into tumors, promoting an immunosuppressive environment.
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Host-Related Factors: Intrinsic factors like age, gender, and gut microbiome composition influence immunotherapy effectiveness. For instance, elderly patients may respond similarly to young patients, while gender differences exist. The gut microbiome, the collection of microorganisms in the digestive system, affects responses to immunotherapy. Specific bacterial species can impact the efficacy of immunotherapy drugs.
Conclusion
Resistance to immunotherapy in rare tumors continues to be a major problem. Despite encouraging developments in immunotherapeutic methods, the intricate interaction of genetic alterations, the tumor microenvironment, and tumor intrinsic and extrinsic variables leads to treatment resistance. Treatment strategies are further complicated by the variability of rare tumors. A thorough understanding of the underlying processes, novel therapeutic techniques that target certain pathways, and individualized treatment plans are necessary in the fight against resistance in rare tumors. Enhancing patient outcomes is possible through collaborative research efforts, clinical trials, and precision medicine breakthroughs.
