International Journal of Clinical Case Reports 2024, Vol.14, No.4, 189-201 http://medscipublisher.com/index.php/ijccr 191 tumor-intrinsic factors that impair immune recognition and attack. One such factor is the loss of function in the PBRM1 gene, which plays a role in chromatin remodeling and has been implicated in reduced responses to PD-1 blockade in RCC. Mutations in PBRM1 lead to altered immune signaling and hinder the recruitment of cytotoxic T cells, limiting their capacity to mount an anti-tumor response (Miao et al., 2018). Other intrinsic resistance mechanisms include defects in the antigen-presentation machinery, such as the loss of beta-2 microglobulin (B2M), which is crucial for MHC class I-mediated antigen presentation. Without proper antigen presentation, the immune system cannot effectively recognize and eliminate cancer cells (Lee et al., 2021). Additionally, tumors can upregulate alternative immune checkpoints, such as TIM-3, LAG-3, and VISTA, which provide redundant inhibitory signals that bypass the blockade of PD-1 or CTLA-4 (Barrueto et al., 2020). These alternative checkpoints suppress immune activation and allow the tumor to escape immune surveillance. The tumor microenvironment (TME) itself can also contribute to primary resistance by promoting an immunosuppressive environment that favors tumor growth. For instance, increased infiltration of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) can inhibit the function of effector T cells, preventing a robust anti-tumor immune response. Overall, primary resistance reflects the tumor's inherent ability to evade immune detection and attack, necessitating the development of combination therapies that target multiple immune pathways simultaneously (Feng et al., 2019). 2.2 Molecular mechanisms of acquired resistance Acquired resistance develops in patients who initially respond to immune checkpoint blockade but later experience disease progression. This form of resistance is typically driven by tumor evolution and changes in the tumor microenvironment that occur in response to immune pressure. One key mechanism of acquired resistance is immune escape, where tumors lose the neoantigens that were initially recognized by the immune system. This loss of neoantigens can occur through genetic mutations or deletions, reducing the immune system’s ability to recognize and target cancer cells effectively. Studies have shown that up to 60% of neoantigens present in primary tumors are no longer detectable in metastatic or resistant tumors, suggesting that immune editing plays a significant role in acquired resistance (Álvarez Ballesteros et al., 2021). Another major contributor to acquired resistance is the remodeling of the immunosuppressive microenvironment. Over time, tumors can recruit higher numbers of immunosuppressive cells, such as Tregs, MDSCs, and tumor-associated macrophages (TAMs), which inhibit the activity of cytotoxic T cells and natural killer (NK) cells. These immunosuppressive cells create a hostile environment that protects the tumor from immune attack. Additionally, tumor cells can upregulate immune checkpoint molecules like PD-L1 in response to interferon signaling, further dampening the immune response (Bi et al., 2021). Acquired resistance can also involve mutations in key immune pathways, such as the JAK/STAT signaling pathway, which regulates immune cell infiltration and activation. Tumors with mutations in JAK2, for example, exhibit reduced sensitivity to immune checkpoint inhibitors, leading to treatment failure. These insights into acquired resistance underscore the dynamic nature of the tumor-immune interaction and highlight the need for adaptive therapeutic strategies. By targeting both tumor-intrinsic mechanisms, such as mutations in antigen presentation pathways, and the immunosuppressive microenvironment, it may be possible to overcome acquired resistance and restore the effectiveness of immune checkpoint blockade (Luyo et al., 2019). 2.3 Identification of biomarkers for resistance to immune checkpoint blockade therapy The identification of reliable biomarkers is essential for predicting which patients will respond to immune checkpoint blockade and for understanding resistance mechanisms. PD-L1 expression has been widely studied as a potential biomarker for response to PD-1/PD-L1 inhibitors, but its predictive value remains limited and inconsistent. Many patients with high PD-L1 expression still fail to respond, while some with low or no PD-L1 expression do benefit from treatment. Therefore, more robust biomarkers are needed to guide clinical decisions. Tumor mutational burden (TMB) is one emerging biomarker, as higher TMB has been associated with better responses to immune checkpoint inhibitors in various cancers, including RCC
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==