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Lee, H.W. Mmunotherapy-Based Rational Combinations for RCC. Encyclopedia. Available online: https://encyclopedia.pub/entry/11181 (accessed on 20 April 2024).
Lee HW. Mmunotherapy-Based Rational Combinations for RCC. Encyclopedia. Available at: https://encyclopedia.pub/entry/11181. Accessed April 20, 2024.
Lee, Hye Won. "Mmunotherapy-Based Rational Combinations for RCC" Encyclopedia, https://encyclopedia.pub/entry/11181 (accessed April 20, 2024).
Lee, H.W. (2021, June 23). Mmunotherapy-Based Rational Combinations for RCC. In Encyclopedia. https://encyclopedia.pub/entry/11181
Lee, Hye Won. "Mmunotherapy-Based Rational Combinations for RCC." Encyclopedia. Web. 23 June, 2021.
Mmunotherapy-Based Rational Combinations for RCC
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22126290

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. 

brain metastases renal cell carcinoma immune checkpoint inhibitors treatment resistance tumor immune microenvironment combination tyrosine kinase inhibitor radiotherapy

1. Introduction

Renal cell carcinomas (RCC) comprise a heterogeneous histologic subtype of malignant neoplasms arising from the nephron, and widely vary with respect to the underlying pathogenesis, genomic/molecular characteristics, and clinical treatment, including the susceptibility to conventional therapeutics [1][2][3][4][5][6][7][8]. Sequential events in the molecular etiopathogenesis of Von Hippel–Lindau (VHL)-inactivated metastatic RCC (mRCC) can be summarized as constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity, fostering global changes in the metabolome, genome, and epigenome in apoptotic, cell cycle regulatory, and mismatch repair pathways, angiogenesis, metabolic adaptations, and immune evasion [1][2][3][4][5][9][10].
Systemic therapy against mRCC has evolved significantly over the past two decades [11][12][13][14]. Vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) (e.g., sunitinib, pazopanib, axitinib, tivozanib, lenvatinib, and cabozantinib) or mammalian target of rapamycin (mTOR) pathway inhibitors (e.g., everolimus and temsirolimus) were used in the 2000s for mRCC, either combined or as a monotherapy [11][12][13][14]. A validation study of the International Metastatic RCC Database Consortium (IMDC) system revealed that the median overall survival (OS) significantly improved in the 2000s as compared to that observed in the cytokine era (favorable risk: 43.2 months, intermediate risk: 22.5 months, and poor risk: 7.8 months) [15]. Unfortunately, the 5-year OS rate for mRCC remains under 30% despite the TKI-based approach [11][12][13][14].

2. Clinical Implications and Unmet Needs of Brain Metastases from RCC

Brain metastases (BM) is generally associated with a very poor prognosis and high degree of morbidity, requiring urgent multidisciplinary care, and is relatively unresponsive to conventional systemic therapy [11][16][17][18][19][20][21][22][23][24][25]. BM is also a serious condition that causes headaches, focal neurological deficits, altered mental status or gradual cognitive impairment, epileptic seizures driven by increased intracranial pressure by vasogenic edema, or alterations in cerebrospinal fluid (CSF) flow, thereby impairing the quality of life (QOL) [11][17][18][19][25][26][27]. Unfortunately, BM is not a rare finding in mRCC (8%–15%), and its prevalence has increased in the past two decades [16][17][18][19][20][21][22]. The median OS of RCC patients with BM (RCC-BM) is only 5–8 months [16][17][18][19][20][21][22]. Therefore, early detection and effective treatment of BM is an unmet medical need for mRCC [11][17][19][25]. Improved clinical outcomes of extracranial metastases by the introduction of TKIs and immune checkpoint inhibitors (ICIs) has led to the adoption of improved imaging techniques for BM, thereby increasing awareness of the benefit of brain screening [11][17][18][19][20][27].
As advances in both local and systemic therapies provide better survival outcomes, mRCC patients with solitary BM and good performance status (PS) can benefit from early detection of asymptomatic BM [11][19][25][28]. Nevertheless, current surveillance guidelines for patients with RCC do not recommend brain imaging, unless BM is clinically suspected [11][29][30]. A large mRCC cohort study to investigate the rate of incidental BM highlighted that a relevant proportion of patients with mRCC (4.3%) may harbor occult BM through brain imaging as a part of eligibility assessments for clinical trial [16]. These data suggested that the risk of asymptomatic brain involvement extends to those with favorable risk features per IMDC risk assessment [16][19]. Sarcomatoid dedifferentiation, T2-4 disease, tumor size >10 cm, regional node involvement, and thoracic and osseous sites of extracranial disease, initial presence with metastatic disease at diagnosis and disease progression during first-line therapies were independent BM-associated risk factors for mRCC [16][19][20][25][31][32]. Consistent evaluation of risk and identification of highly sensitive and accurate algorithmic screening approaches are required to characterize mRCC patients with a considerably high propensity for BM, given that early detection may improve clinical outcomes and decrease the potential risks of aggressive multimodality treatment in patients with mRCC [11][16][19][25][28][31].
Unfortunately, brain lesions may be detected only after establishment of a microenvironment supportive of tumor growth and visible proliferation using magnetic resonance imaging (MRI) or computed tomography scans; however, these technologies are not sensitive enough to detect very early metastases [11][19][25][28]. Alternative approaches that can enable early diagnoses of BM are thus being explored based on liquid biopsy of circulating tumor DNA obtained from the CSF [33]. The implications of liquid biopsies for BM are notable, as they facilitate early detection and molecular profiling of a brain lesion to initiate the most appropriate treatment. Finally, prognostic factors are important for determining the optimal treatment modality for RCC-BM [11].

3. Immunosuppressive Pro-Metastatic Brain-Specific Tumor Microenvironment (TME)

The immune landscape of RCC-BM is less characterized than those of primary brain cancers [34][35]. The central nervous system (CNS) is protected by several functional barriers, including the blood–brain barrier (BBB) and blood–CSF barrier [34][35][36][37]. The BBB consists of endothelial cells with low transcytosis rates and high expression of efflux pumps that are connected by continuous tight junctions [34][35][36][37]. In addition, two basement membranes, embedded pericytes, and astrocytic terminal processes contribute to the BBB functions [34][35][36][37]. By comparison, the blood–CSF barrier is formed by choroid plexus epithelial cells that are connected via tight junctions, with choroid plexus capillaries having fenestrations and intercellular gaps that enable the free movement of molecules between these compartments [34][35][36][37]. Diffusion restriction of systemic agents into the CNS is considered a potential obstacle for intracranial efficacy of multiple TKIs and ICIs [16]. However, in patients with BM, the BBB is leaky and is substituted by a blood–tumor barrier (BTB) with a wider fenestration, leading to a higher efflux of fluid [17][34][37][38][39].
The development of BM disrupts the BBB damaged by a prominent neuroinflammatory response and anti-tumor treatment, such as surgery and/or radiotherapy, and is often characterized by abnormal vascular sprouting, allowing an influx of circulating myeloid and lymphoid cells, which are generally absent in the brain parenchyma, into the CNS [17][27][35][37][38]. The composition of the brain-specific immunosuppressive TME revealed cancer-specific enrichment of immune cells with pronounced differences in proportional abundance of microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells, playing a major role in BM progression, and creating a multitude of potential targets [38].
CNS myeloids, microglia and border-associated myeloid cells (BAMs), vitally contribute to brain homeostasis and diseases [38][40][41]. At homeostasis, microglia are the brain’s equivalent of tissue-resident macrophages, representing 5%–15% of adult brain cells [37][40][41]. BAMs reside specifically in the meninges, choroid plexus, or perivascular macrophages associated with blood vessels [34][37][38][42]. Microglia and BAMs have different gene expression signatures, with BAMs being characterized by high CD38 and major histocompatibility complex (MHC) class Ⅱ, thus supporting their role as antigen presenting cells [34][38][42]. In addition, peripheral bone marrow-derived myeloid cells (BMDMs) may infiltrate the brain parenchyma and contribute to neuroinflammation [38][42]. CNS myeloids promote BM via chemokine (C-X-C motif) ligand 10 (Cxcl10) signaling and negative immune checkpoints that foster an immune suppressive niche, indicating blocking V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) and programmed cell death ligand 1 (PD-L1) signaling as an effective immune strategy [34][35][37][38][42].
Another predominant (up to 30% of the tumor mass) immune subset of BM TME are tumor-associated macrophage (TAM)-peripheral bone marrow-derived myeloid cells (BMDMs) [34][35][37][38][42]. They can be localized in the advancing tip of the tumor, blood vessels, or perinectrotic areas, where they play a role in tumor cell motility, establishment of metastatic niche, or angiogenesis, respectively [34][35][37][38][42]. Tissue-invading TAM-BMDMs with complex multifaceted phenotypes show a distinctive signature trajectory, revealing tumor-driven instructions along with contrasting tumor-infiltrating lymphocyte (TIL) activation and exhaustion [34][38][42]. When stimulated and reprogrammed by cancer cells, TAM-BMDMs can secrete immunosuppressive biomolecules, including transforming growth factor-β (TGF-β), interleukin (IL)-10, and arginase [37][43]. As TAM-BMDMs are implicated in BM promotion and exhibit gene signatures that are associated with wound healing, antigen presentation, and immune suppression [34][35][38][42], selective depletion or blockade of TAM-BMDM recruitment could lead to effective T cell activation and execution of anti-tumor effector functions [27][34][38][42].
A range of lymphoid cells, including B and T cells, as well as innate lymphoid, natural killer (NK), and NK T cells, may be found within the CSF of the meninges, choroid plexus, and ventricles, although they are absent from the brain parenchyma [27][37][40]. RCC-BM leads to a moderate T cell influx, and T cells are predominantly localized within the stromal compartments of the tumor [35]. Tumor cells may also produce indolamine 2,3-dioxygenase (IDO), which stimulates the accumulation of regulatory T cells (Treg) and suppresses T cell activity by depleting tryptophan from the TME [37][38][42][44]. Importantly, the presence of PD-L1+ TAMs has been correlated with Treg frequencies in several solid tissue tumors [38][42][45]. Tregs secrete IL-10, IL-4, and IL-13, which may trigger the development of TAMs with immunosuppressive properties and suppression of cytotoxic CD8+ T cell responses [38][42][46]. The major changes in T cell activation in BM are the activation and exhaustion of CD8 tissue resident memory and effector memory subsets, displaying high amounts of both co-stimulatory and co-inhibitory molecules, as well as proliferation markers [35][38][42].

4. Multimodal ICI-Based Therapeutic Strategies for RCC-BM

RCC-BM poses unique clinical challenges because treatment of BM is complex, and a variety of factors, including anticipated patient survival, competing risks, and long-term toxicities should be considered while selecting the appropriate treatment strategy [11][17][47]. The brain, being a vital organ, is unable to regenerate upon damage, thus accounting for major limitations for therapy [11][17][47][48]. For instance, neurosurgery cannot always be performed, and radiotherapy has the risk of irreversibly limiting brain plasticity, which could evolve into a potentially lethal radionecrosis [48]. Three key indicators favor a good prognosis and thus more aggressive treatment: a KPS score > 70, age < 65 years, and controlled extracranial metastases [47][49].
The current approach for RCC-BM typically includes surgery (pathologic diagnosis and cerebral decompression) versus standalone radiotherapy and/or systemic therapies, with the overall goal of selecting the optimal treatment for an individual patient to maximize QOL and survival outcomes [17][47][48][49][50]. Surgery and radiation are the mainstays of therapy and have proven neurological and palliative benefits [17][47][49][50][51]. Medical therapies for RCC-BM can be divided into two broad categories: symptomatic management and tumor-targeting therapies. Corticosteroids, such as dexamethasone, represent the main symptomatic treatment in addition to pain medications because of their minimal mineralocorticoid effect and control intracerebral edema in BM [17]; however, the beneficial effects of steroids are not permanent, and a rapid taper is typically recommended to minimize drug-related adverse effects [17]. In addition, increased understanding of the role of immunosuppression in the pathophysiology of metastatic diseases reveals the potential harm of steroid-associated immunosuppression, thereby encouraging minimal steroid exposure and alternatives to steroid therapy [17].

4.1. ICIs Based on T Cell Exhaustion in RCC-BM

Although most patients with RCC-BM are excluded from important clinical trials because of poor prognosis and few validated treatment guidelines [11][48], this trend is diminishing given the increasing importance of clinical significance and a better knowledge of the underlying pathogenesis. The remaining majority of systemic therapies for RCC-BM dramatically changed with the introduction of ICIs and TKIs based on complex microenvironmental niche–tumor interactions, neuroinflammatory cascades, and neovascularization involved in establishing a new BM [11][17][47][48]. The richness and activation of BM TMEs regarding cellular subtypes, frequencies, and functional states parallels their favorable clinical response to ICIs [42]. Checkpoint interactions, such as PD-1:PD-L1, CTLA4:B7-1/2, T-cell immunoglobulin and mucin domain-3 (TIM-3):Galectin-9, and lymphocyte activation gene-3 (LAG-3):MHC class Ⅱ, play an important role in immune evasion of cancers [1]. Drug Administration (FDA) for mRCC include those that block co-inhibitory molecules, such as cytotoxic T-lymphocyte activating protein-4 (CTLA-4), PD-1, and PD-L1, thus facilitating T cell effector function and anti-tumor response [52][53].
Costimulation with CD28 or 4-1BB can increase anti-tumor activity [54][55]. CD28 costimulation can increase T cell anabolic metabolism, while the CD28 family members PD-1 and CTLA4 suppress T cell metabolic reprogramming [54]. CTLA4 inhibits CD28 signaling and PI3K/Akt/mTORC1 signaling, resulting in decreased glycolysis and mitochondrial oxidative capacity [56]. Blocking the negative regulators of PD-1 and CTLA4 that impair CD28 signaling to inhibit T cell release facilitates anti-tumor activity [54]. CD8+ T cells continuously formulate their exhaustion states on account of exposure to suppressive gradients in the TME [57]. T cell exhaustion is the conversion of the state of CD8+ T cells from antineoplastic to immune-functionally impaired due to long-term persistence of tumor antigens and/or the suppressive TME [58][59]. The exhausted CD8+ T-cell phenotype has been associated with an increased risk of tumor progression [60][61], increased dysfunctional dendritic cells (DCs) [62], and elevated numbers of immune cells, namely M2-polarized macrophages, resting mast cells, resting memory CD4+ T cells, and CD4+ Foxp3+ Tregs [60][63][64][65]. Coinhibitory receptors, such as PD-1 and CTLA-4, are traditionally envisioned as exhaustion markers of T cells [59][66], which is the theoretical ICB.
Additionally, the prognostic impact of exhausted CD8+ T cell infiltration in mRCC is only through stratification into specific subgroups [60][62][64][67][68][69][70]. For example, CXCL13+ CD8+ T cells exhibit elevated levels of markers, such as PD-1, Tim-3, T cell immunoreceptor with Ig and ITIM domains (TIGIT) and CTLA-4, higher Ki-67 expression, and lower levels of activated markers, such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) [67][71]. Furthermore, the abundance of intratumoral CXCL13+ CD8+ T cells was positively correlated with immunoevasive TME accompanied by increased T helper 2 cells, TAMs, CD4+ Foxp3+ Tregs, and decreased NK cells [67]. The HIF-1-TGF-β pathway might serve as a crucial molecule in connecting CXCL13+ CD8+ T cells and TME, [67][72][73][74]. Neoantigen reactivity is coupled to a CXCL13-secreting ‘‘exhausted’’ phenotype, possibly induced by chronic TCR signaling [75]. The selective expression of CCR5 and CXCL13 in neoantigen-specific T cells further suggests that a key feature of ICI-responsiveness is the ability to sustain ongoing priming and recruitment of tumor reactive T cells supported by CXCR5+ lymphocytes [76][77]. Interestingly, patients with higher numbers of CD39+ CD8+ T cells showed improved responses to sunitinib, a multi-TKI, suggesting that evaluation of the exhausted phenotype for CD8+ T cells may help in clinical decision making or therapy selection [61].
Many receptors in the immunoglobulin superfamily (such as CD28, and inducible T cell co-stimulator) and TNF receptor superfamily (TNFSF) exert costimulatory actions [78]. TNFSRF9 is thought to be an antigen stimulation-inducible co-stimulatory receptor, which is transiently expressed on activated CD8+ T, activated CD4+ T, and NK cells [64][79][80]. Co-stimulatory signaling mediated by TNFRSF9 promotes T cell proliferation, secretion of cytokines, resistance to activation-induced cell death, and development of memory T cells [80]. TNFRSF9+ CD8+ T cells possess both exhaustion (PD-1, TIM-3, CTLA-4, and TIGIT) and effector phenotype (IFN-γ, granzyme B, and Ki-67) [79]. This dual phenotype of TNFRSF9+ CD8+ T cells indicates that these cells may not be terminally exhausted; however, they could respond to ICB [79]. The functional status of TNFRSF9+ CD8+ T cells might partly result from the complicated interactions among immune cells (helper T cells, CD8+ T cells, and myeloid cells) within the tumor, and high enrichment of TNFRSF9+ CD8+ T cells could be a predictor of immunotherapy and a novel therapeutic target in mRCC [79].

4.2. ICIs Based on Targeting Immunometabolomics in RCC-BM

RCC is essentially a metabolic disease characterized by a reprogramming of energetic metabolism, and many genes that are mutated in RCC encode proteins that have roles in cellular processes regulating oxygen and glucose consumption [54]. In particular the metabolic flux through glycolysis is partitioned [81][82][83][84], and mitochondrial bioenergetics and oxidative phosphorylation are impaired, as well as lipid metabolism [82][85][86]. In addition, RCC is one of the most immune-infiltrated tumors [87][88]. Emerging evidence suggests that the activation of specific metabolic pathway have a role in regulating angiogenesis and inflammatory signatures [89][90]. Features of the TME heavily affect disease biology and may affect responses to systemic therapy [91]. VHL mutations that occur in mRCC increased transcriptional activity of its target genes, such as VEGF, glucose transporter 1, and erythropoietin, independent of oxygen levels, promoting angiogenesis, and immunosuppression [54]. The complexity of cellular interactions and depletion of available nutrients may create an environment of nutrient competition for T cells, and buildup of waste products that may impair T cells [92]. RCC-BM demonstrated metabolic changes leading to alterations in pathways associated with energy metabolism and oxidative stress, as well as the accumulation of immunosuppressive metabolites, such as tryptophan (TRP) [54][92]. Enhanced activity across an array of interconnected oncogenic signaling networks centered on the PI3K-AKT pathway represents a generalizable feature across different BM histologies [92].
The analysis of metabolic pathways intrinsic to immune cell types, also known as immunometabolism, could identify markers of immune function based on the distinct metabolic requirements of these cells at each stage of differentiation [93]. At the single-cell level, costimulation shifted the percentage of cells from a baseline resting state into two primary branches: one that was enriched in IL-2 signaling and glycolysis and another that exhibited pathways of glycolysis, oxidative phosphorylation, and Myc signaling [54]. This bioenergetic switch is consistent with the known Myc regulation of metabolic reprogramming during T cell activation [54]. Activation, together with signaling through the costimulatory molecule CD28, augments signaling through the PI3K/Akt/mTORC1 pathway to increase glucose and mitochondrial metabolism, and enable robust proliferation and effector function [94][95].
Metabolic reprogramming dictates the fate and function of stimulated T cells and microenvironment of tumors coupled with chronic exposure to neoantigens can impair the metabolism of TILs [54][96][97]. Stimulated T cells are highly dependent on metabolic reprogramming from catabolic oxidative metabolism to anabolic metabolism with elevated glucose consumption and aerobic glycolysis to develop effector functions [98][99][100]. T cell activation leads to increased Myc and PI3K/Akt/mTORC1 signaling activity to promote glucose uptake and mitochondrial metabolism for growth and energetics, and to regulate signaling and gene expression pathways [95][101][102]. CD8+ T cells in RCC can be subject to metabolic barriers that lead to adaptations, such as reduced ability to absorb glucose for downstream glycolysis, fragmented and functionally altered mitochondria with low respiratory capacity, and elevated production of reactive oxygen species (ROS) [97][103]. These changes are critical for effector T cell function, as CD8+ PD-1+ cells subject to inhibition of glucose metabolism fail to develop into effector subsets and have a reduced capacity to favor suppressive Treg fates [54][103]. RCC CD8+ TILs have altered metabolic and functional parameters, suggesting reduced metabolism and failure of antigen receptor stimulation to activate a predominant effector memory phenotype [54].
In addition, PD-1 signaling suppresses T cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation (FAO) [54][56]. While CD8+ RCC TIL gene expression exhibits classical markers of chronic stimulation and enrichment of metabolic pathways, including FAO, glycolysis, and cholesterol homeostasis, a large portion of cells could be stimulated to reprogram metabolism and induce effector functions [54]. The link between very long chain fatty acid-containing lipids and response to ICI in RCC can be explained by enhanced peroxisome signaling in activated T cells, which leads to a metabolic switch to fatty acid catabolism [104]. Lastly, increased conversion of TRP to kynurenine by IDO leads to inhibition of T cell function and is involved in the regulation of the immunosuppressive TME of mRCC [54][105].

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