Abstract
Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.
Keywords: sarcoma, lactate, microenvironment, acidity, immune response
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072766/
Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
1. Introduction
Sarcomas are rare malignancies (12% of all human cancers) of mesenchymal origin. Although there exist more than 70 subtypes, it is possible to divide them into two main categories: soft tissue sarcomas (STSs), which are derived from fat, muscle, nerve, sheath and blood vessels, representing less than 1% of all new cancer diagnoses, and bone sarcomas [1,2]. Among STSs, liposarcoma (LPS) and undifferentiated pleomorphic sarcoma are the most common subtypes in adults, while rhabdomyosarcoma is one of the highest incidences of tumors in children [3,4]. Concerning bone sarcomas, Ewing’s sarcoma (EWS) is one of the most frequently diagnosed in children together with osteosarcoma (OS), which is also a common subtype in adults as well as chondrosarcoma [5]. In addition to different histological genesis, sarcomas are characterized by high genetic instability and molecular heterogeneity [6]. To date, conventional therapies are based on surgical resection followed by radio- and chemotherapies, but mortality still remains unchanged, since sarcomas often develop recurrences and resistance to treatments. New diagnostic and therapeutic strategies are critically needed.
Recently, studies on targeted therapies involving the tumor microenvironment (TME) are acquiring increasingly prominent. Indeed, the sarcoma microenvironment is a very complex and dynamic milieu, characterized mainly by high interstitial acidosis and high-density immune infiltrate. In this context lactate, the end-product of fermentative glycolysis released by both cancer cells and TME components is emerging as a key player of tumor progression, besides, its metabolic role is known, affecting the invasive abilities of cancer cells, the angiogenic process as well as the immune response [7].
High lactate levels and elevated immune infiltrate of the sarcoma microenvironment could be the basis for a remarkable source of therapeutic targets and future promising clinical trials.
Sarcomas are rare malignancies (12% of all human cancers) of mesenchymal origin. Although there exist more than 70 subtypes, it is possible to divide them into two main categories: soft tissue sarcomas (STSs), which are derived from fat, muscle, nerve, sheath and blood vessels, representing less than 1% of all new cancer diagnoses, and bone sarcomas [1,2]. Among STSs, liposarcoma (LPS) and undifferentiated pleomorphic sarcoma are the most common subtypes in adults, while rhabdomyosarcoma is one of the highest incidences of tumors in children [3,4]. Concerning bone sarcomas, Ewing’s sarcoma (EWS) is one of the most frequently diagnosed in children together with osteosarcoma (OS), which is also a common subtype in adults as well as chondrosarcoma [5]. In addition to different histological genesis, sarcomas are characterized by high genetic instability and molecular heterogeneity [6]. To date, conventional therapies are based on surgical resection followed by radio- and chemotherapies, but mortality still remains unchanged, since sarcomas often develop recurrences and resistance to treatments. New diagnostic and therapeutic strategies are critically needed.
Recently, studies on targeted therapies involving the tumor microenvironment (TME) are acquiring increasingly prominent. Indeed, the sarcoma microenvironment is a very complex and dynamic milieu, characterized mainly by high interstitial acidosis and high-density immune infiltrate. In this context lactate, the end-product of fermentative glycolysis released by both cancer cells and TME components is emerging as a key player of tumor progression, besides, its metabolic role is known, affecting the invasive abilities of cancer cells, the angiogenic process as well as the immune response [7].
High lactate levels and elevated immune infiltrate of the sarcoma microenvironment could be the basis for a remarkable source of therapeutic targets and future promising clinical trials.
Debbie
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Sarcoma Microenvironment
Cancer cells can educate the stromal cells resident in the microenvironment to its own benefits. The TME is characterized by a heterogeneous cell population that contributes to enhancing tumor growth, progression and aggressiveness by secretion of growth factors, hormones, cytokines and extracellular matrix and by an interaction between cell surface receptors and adhesive ligands [8,9].
The sarcoma microenvironment is a highly vascularized mesenchymal tissue, mainly represented by mesenchymal stem cells (MSCs), which exert a key role in sarcoma onset and progression [10,11], and by tumor-infiltrating immune cells, which affect cancer outcome and prognosis (Figure 1).
Figure 1
Figure 1
Lactate has a key role in cancer progression. Microenvironmental secreted lactate increases angiogenesis, motility and migration of cancer cells. Lactate is directly involved in the ‘immune escape’ by decreasing activation of T cells and ...
MSCs can differentiate towards diverse types of cell such as myofibroblast-like cells, pericyte-like cells, chondrocytes, adipocytes, osteocytes, cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs). Increasing evidence suggest that MSCs might be the tumor initiating cells, namely the origin of a spectrum of sarcomas, both pleomorphic and translocation-driven subtypes, although there is still a great controversy about this aspect. Together with oncogenic events that occur during MSCs differentiation, it is well recognized a prominent role of the microenvironment that favors malignancies development, strengthening the “seed and soil” theory [12]. Previous studies have produced controversial results about the role of MSCs in tumor progression: especially whether MSCs support or suppress tumor growth. Despite this old dispute, it is now clear that systemically administered MSCs are recruited to tumors. Indeed, tumors and their TME prompt MSCs recruitment through different mechanisms that depend mainly on various inflammatory cytokines, chemokines and growth factors [13]. Moreover, several studies report that subsequently to MSC recruitment, tumor tissues educate MSCs to adopt a tumor-growth promoting phenotype [13]. In response to tumor derived acidity, resident MSCs are reprogrammed to tumor tissue-derived MSCs (t-MSCs), which further increase local acidification sustaining tumor progression [14,15]. Several studies demonstrated that MSCs induce pro-proliferative effects on tumor cells, promote OS stemness and epithelial to mesenchymal transition (EMT), recruit immunosuppressive cells and support tumor angiogenesis [16,17]. Our group has demonstrated that OS cells promote bone marrow derived-MSCs homing by production of monocyte chemoattractant protein-1 (MCP-1), growth-regulated oncogene-α (GRO-α) and transforming growth factor-β1 (TGF-β1). Once recruited inside the tumor lesion, in response to tumor-secreted cytokines, MSCs stimulate stemness, invasiveness and mesenchymal to amoeboid transition in OS cells, increasing their transendothelial migration. Furthermore, MSCs-stimulated OS cells increase the expression of pro-angiogenetic factors and promote migration, invasion and formation of the capillary network of endothelial cells in vitro [18]. Moreover, between MSCs and sarcoma cells a strict cross-talk is established: really, local tumor-derived acidosis, as well as, tumor associated osteolysis exert a great impact on MSC stemness [14,15]. Also lactate, the main driver of tumor acidosis, has a key role in OS progression: Bonucelli G. et al. demonstrated that MSCs are induced by adjacent OS cells to undergo Warburg metabolism and hence to increase lactate production and monocarboxylate transporter 4 (MCT4) expression. Thus, MSC-derived lactate feeds OS. Indeed, OS cells, through MCT1, import lactate, which drives mitochondrial biogenesis and promotes the migratory skill of OS cells. Probably, the role of lactate in this context is not only to fuel OS but rather to acidify the medium, thereby supporting a metastatic phenotype [19,20].
Confirming the role of MSCs in sustaining tumor progression, it has been demonstrated that in the sarcoma microenvironment, MSCs are more abundant than in adjacent normal tissue, this phenomenon is particularly evident in OS [21]. In keeping, in EWS tissues, tumor infiltrating MSCs are more proliferative than normal MSCs and have high expression of proliferation genes respect to normal MSCs [22].
Of note, MSCs exhibit unique immunomodulatory properties [23]. Through the secretion of paracrine factors, such as growth factors, cytokines and exosomes, or by cell-to-cell contacts, MSCs may affect the behavior of different immune cell types, including T and B-lymphocytes, monocytes, macrophages and dendritic cells [23,24,25]. MSCs are able to inhibit CD4+ and CD8+ proliferation, to decrease cytokines production by CD4+ and to suppress cytotoxic activity of CD8+ and natural killer (NK) cells [26]. Furthermore, MSCs stimulate polarization of T cells toward the regulatory phenotype, supporting their immunosuppressive functions [27,28]. It has also been proved that MSC-derived exosomes inhibit the activation and proliferation of B cells and reduce immunoglobulin secretion [29,30]. In addition, MSCs promote M2 macrophage polarization and inhibit chemotaxis of monocytes within the inflammatory lesion [23,31,32]. Finally, MSCs cooperate in the recruitment, maturation and function of dendritic cells, the most important antigen presenting cells in the body [33,34,35].
Consequently, by modulating the composition of the immune infiltrate, MSCs play a prominent role in many types of sarcoma. Indeed, several studies highlighted that the immune component of TME is crucial in determining the overall survival, prognosis and response to the therapy of several types of sarcoma. In EWS sarcoma, CD8+ cells infiltration correlates with improved survival [5]; also in several STSs including gastrointestinal stromal tumor (GIST), leiomyosarcoma, cutaneous angiosarcoma, high-grade undifferentiated pleomorphic sarcoma and synovial sarcoma, the presence of tumor-infiltrating lymphocytes correlates with improved prognosis [36,37,38]. In a mouse model of spontaneous GIST, the immune system cooperates substantially with Imatinib therapy. Indeed, Imatinib activates CD8+ T cells and induces regulatory T (Treg) apoptosis inside the tumor. Coherently, the CD8+ T cell to Treg ratio in human GISTs specimen with acquired resistance to Imatinib is significantly lower than in sensitive tumors [39].
Conversely to cytotoxic cells infiltrates, which exert a tumor suppressive action, the presence of TAMs and Tregs in the TME of different sarcoma types correlate with a worse prognosis. High density of both M2-polarized TAMs and Tregs has been shown in GIST, EWS, uterine and non-uterine LPS and myxoid LPS [40,41,42,43,44]. In OS, IL-34 production contributes to tumor growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages [45]. Interestingly, in a xenograft human OS model, Xiao Q. et al. demonstrated that the recruited macrophages were polarized toward M2 subtype and tumor growth was strongly inhibited by the specific deletion of this cell population [46].
In addition, the expression on tumor cells of the checkpoint protein programmed death-ligand 1 (PD-L1) and the infiltration of programmed cell death protein 1 (PD1)-positive lymphocytes have been studied as a potential prognostic factor in sarcomas. In OS patients, the progression of the disease has been associated with the presence of the suppressive receptor PD1 on peripheral CD4+ and CD8+ T cells [47]. Furthermore, Kim C. et al. analyzed the relevance of the intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in a cohort of 105 patients bearing of STSs. The presence of both intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were significantly associated with higher clinical and histological stage, presence of distant metastasis and poor tumor differentiation [48]. Indeed, immune checkpoint inhibitors, which have emerged as encouraging therapy in other tumor types, are now tested in a range of sarcoma subtypes either as single agents or in combination with chemotherapy or kinase inhibitors [49].
The sarcomas TME is also rich with immunosuppressive cytokines including vascular endothelial growth factor (VEGF) that, together with hypoxia-inducible factor-1 α (HIF-1α), inhibits the maturation of dendric cells and promotes M2 macrophages and Treg migration inside the tumor stroma [50,51]. Indeed, in sarcomas high expression of VEGF and hypoxia correlate with poor prognosis and resistance to chemotherapy [52].
Moreover, high concentrations of indole 2,3-dioxygenase 1 (IDO1), which promotes the expression of kynurenine, thus stabilizing Tregs and suppressing the activity of cytotoxic T cells [53], correlate with lower metastasis-free survival and overall survival in sarcoma patients. In GST, Imatinib potentiates the anti-tumor T cell response through the inhibition of IDO [39].
In summary, these data show that most sarcomas exhibit immune cell infiltrates, but the tumor and immune microenvironment tends to be immunosuppressive. A deep investigation to underscore which kind of immune cells populate the TME and their role in tumor progression will be fundamental for prognosis and survival, to predict the response to immunotherapy and to develop new strategies to defeat tumors.
A second essential aspect of sarcoma microenvironment is the strong extracellular acidification. Indeed, deregulation of acidity, especially lactic acidosis, is crucial to promote tumor growth and metastasis, as already reported for sarcomas and other cancer types [15,54,55]. In this light, we first illustrate the main role of lactate as general driver of tumor progression based on the recent literature and then we deeply analyze its specific role in the field of sarcoma biology.
Cancer cells can educate the stromal cells resident in the microenvironment to its own benefits. The TME is characterized by a heterogeneous cell population that contributes to enhancing tumor growth, progression and aggressiveness by secretion of growth factors, hormones, cytokines and extracellular matrix and by an interaction between cell surface receptors and adhesive ligands [8,9].
The sarcoma microenvironment is a highly vascularized mesenchymal tissue, mainly represented by mesenchymal stem cells (MSCs), which exert a key role in sarcoma onset and progression [10,11], and by tumor-infiltrating immune cells, which affect cancer outcome and prognosis (Figure 1).
Figure 1
Figure 1
Lactate has a key role in cancer progression. Microenvironmental secreted lactate increases angiogenesis, motility and migration of cancer cells. Lactate is directly involved in the ‘immune escape’ by decreasing activation of T cells and ...
MSCs can differentiate towards diverse types of cell such as myofibroblast-like cells, pericyte-like cells, chondrocytes, adipocytes, osteocytes, cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs). Increasing evidence suggest that MSCs might be the tumor initiating cells, namely the origin of a spectrum of sarcomas, both pleomorphic and translocation-driven subtypes, although there is still a great controversy about this aspect. Together with oncogenic events that occur during MSCs differentiation, it is well recognized a prominent role of the microenvironment that favors malignancies development, strengthening the “seed and soil” theory [12]. Previous studies have produced controversial results about the role of MSCs in tumor progression: especially whether MSCs support or suppress tumor growth. Despite this old dispute, it is now clear that systemically administered MSCs are recruited to tumors. Indeed, tumors and their TME prompt MSCs recruitment through different mechanisms that depend mainly on various inflammatory cytokines, chemokines and growth factors [13]. Moreover, several studies report that subsequently to MSC recruitment, tumor tissues educate MSCs to adopt a tumor-growth promoting phenotype [13]. In response to tumor derived acidity, resident MSCs are reprogrammed to tumor tissue-derived MSCs (t-MSCs), which further increase local acidification sustaining tumor progression [14,15]. Several studies demonstrated that MSCs induce pro-proliferative effects on tumor cells, promote OS stemness and epithelial to mesenchymal transition (EMT), recruit immunosuppressive cells and support tumor angiogenesis [16,17]. Our group has demonstrated that OS cells promote bone marrow derived-MSCs homing by production of monocyte chemoattractant protein-1 (MCP-1), growth-regulated oncogene-α (GRO-α) and transforming growth factor-β1 (TGF-β1). Once recruited inside the tumor lesion, in response to tumor-secreted cytokines, MSCs stimulate stemness, invasiveness and mesenchymal to amoeboid transition in OS cells, increasing their transendothelial migration. Furthermore, MSCs-stimulated OS cells increase the expression of pro-angiogenetic factors and promote migration, invasion and formation of the capillary network of endothelial cells in vitro [18]. Moreover, between MSCs and sarcoma cells a strict cross-talk is established: really, local tumor-derived acidosis, as well as, tumor associated osteolysis exert a great impact on MSC stemness [14,15]. Also lactate, the main driver of tumor acidosis, has a key role in OS progression: Bonucelli G. et al. demonstrated that MSCs are induced by adjacent OS cells to undergo Warburg metabolism and hence to increase lactate production and monocarboxylate transporter 4 (MCT4) expression. Thus, MSC-derived lactate feeds OS. Indeed, OS cells, through MCT1, import lactate, which drives mitochondrial biogenesis and promotes the migratory skill of OS cells. Probably, the role of lactate in this context is not only to fuel OS but rather to acidify the medium, thereby supporting a metastatic phenotype [19,20].
Confirming the role of MSCs in sustaining tumor progression, it has been demonstrated that in the sarcoma microenvironment, MSCs are more abundant than in adjacent normal tissue, this phenomenon is particularly evident in OS [21]. In keeping, in EWS tissues, tumor infiltrating MSCs are more proliferative than normal MSCs and have high expression of proliferation genes respect to normal MSCs [22].
Of note, MSCs exhibit unique immunomodulatory properties [23]. Through the secretion of paracrine factors, such as growth factors, cytokines and exosomes, or by cell-to-cell contacts, MSCs may affect the behavior of different immune cell types, including T and B-lymphocytes, monocytes, macrophages and dendritic cells [23,24,25]. MSCs are able to inhibit CD4+ and CD8+ proliferation, to decrease cytokines production by CD4+ and to suppress cytotoxic activity of CD8+ and natural killer (NK) cells [26]. Furthermore, MSCs stimulate polarization of T cells toward the regulatory phenotype, supporting their immunosuppressive functions [27,28]. It has also been proved that MSC-derived exosomes inhibit the activation and proliferation of B cells and reduce immunoglobulin secretion [29,30]. In addition, MSCs promote M2 macrophage polarization and inhibit chemotaxis of monocytes within the inflammatory lesion [23,31,32]. Finally, MSCs cooperate in the recruitment, maturation and function of dendritic cells, the most important antigen presenting cells in the body [33,34,35].
Consequently, by modulating the composition of the immune infiltrate, MSCs play a prominent role in many types of sarcoma. Indeed, several studies highlighted that the immune component of TME is crucial in determining the overall survival, prognosis and response to the therapy of several types of sarcoma. In EWS sarcoma, CD8+ cells infiltration correlates with improved survival [5]; also in several STSs including gastrointestinal stromal tumor (GIST), leiomyosarcoma, cutaneous angiosarcoma, high-grade undifferentiated pleomorphic sarcoma and synovial sarcoma, the presence of tumor-infiltrating lymphocytes correlates with improved prognosis [36,37,38]. In a mouse model of spontaneous GIST, the immune system cooperates substantially with Imatinib therapy. Indeed, Imatinib activates CD8+ T cells and induces regulatory T (Treg) apoptosis inside the tumor. Coherently, the CD8+ T cell to Treg ratio in human GISTs specimen with acquired resistance to Imatinib is significantly lower than in sensitive tumors [39].
Conversely to cytotoxic cells infiltrates, which exert a tumor suppressive action, the presence of TAMs and Tregs in the TME of different sarcoma types correlate with a worse prognosis. High density of both M2-polarized TAMs and Tregs has been shown in GIST, EWS, uterine and non-uterine LPS and myxoid LPS [40,41,42,43,44]. In OS, IL-34 production contributes to tumor growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages [45]. Interestingly, in a xenograft human OS model, Xiao Q. et al. demonstrated that the recruited macrophages were polarized toward M2 subtype and tumor growth was strongly inhibited by the specific deletion of this cell population [46].
In addition, the expression on tumor cells of the checkpoint protein programmed death-ligand 1 (PD-L1) and the infiltration of programmed cell death protein 1 (PD1)-positive lymphocytes have been studied as a potential prognostic factor in sarcomas. In OS patients, the progression of the disease has been associated with the presence of the suppressive receptor PD1 on peripheral CD4+ and CD8+ T cells [47]. Furthermore, Kim C. et al. analyzed the relevance of the intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in a cohort of 105 patients bearing of STSs. The presence of both intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were significantly associated with higher clinical and histological stage, presence of distant metastasis and poor tumor differentiation [48]. Indeed, immune checkpoint inhibitors, which have emerged as encouraging therapy in other tumor types, are now tested in a range of sarcoma subtypes either as single agents or in combination with chemotherapy or kinase inhibitors [49].
The sarcomas TME is also rich with immunosuppressive cytokines including vascular endothelial growth factor (VEGF) that, together with hypoxia-inducible factor-1 α (HIF-1α), inhibits the maturation of dendric cells and promotes M2 macrophages and Treg migration inside the tumor stroma [50,51]. Indeed, in sarcomas high expression of VEGF and hypoxia correlate with poor prognosis and resistance to chemotherapy [52].
Moreover, high concentrations of indole 2,3-dioxygenase 1 (IDO1), which promotes the expression of kynurenine, thus stabilizing Tregs and suppressing the activity of cytotoxic T cells [53], correlate with lower metastasis-free survival and overall survival in sarcoma patients. In GST, Imatinib potentiates the anti-tumor T cell response through the inhibition of IDO [39].
In summary, these data show that most sarcomas exhibit immune cell infiltrates, but the tumor and immune microenvironment tends to be immunosuppressive. A deep investigation to underscore which kind of immune cells populate the TME and their role in tumor progression will be fundamental for prognosis and survival, to predict the response to immunotherapy and to develop new strategies to defeat tumors.
A second essential aspect of sarcoma microenvironment is the strong extracellular acidification. Indeed, deregulation of acidity, especially lactic acidosis, is crucial to promote tumor growth and metastasis, as already reported for sarcomas and other cancer types [15,54,55]. In this light, we first illustrate the main role of lactate as general driver of tumor progression based on the recent literature and then we deeply analyze its specific role in the field of sarcoma biology.
Debbie
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Neutralization of tumor acidity improves anti-tumor responses to immunotherapies
Abstract
Cancer immunotherapies, such as immune checkpoint blockade or adoptive T cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of anti-tumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy immunotherapy. An acidic pH environment blocked T cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was post-translational. Acidification did not affect cytoplasmic pH, such that signals transduced by external acidity were like mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T cell infiltration. Further, combining bicarbonate therapy with anti-CTLA-4, anti-PD1 or adoptive T cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.
Abstract
Cancer immunotherapies, such as immune checkpoint blockade or adoptive T cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of anti-tumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy immunotherapy. An acidic pH environment blocked T cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was post-translational. Acidification did not affect cytoplasmic pH, such that signals transduced by external acidity were like mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T cell infiltration. Further, combining bicarbonate therapy with anti-CTLA-4, anti-PD1 or adoptive T cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.
https://www.ncbi.nlm.nih.gov/pmc/articl ... ort=readerBicarbonate is an essential component of the physiological pH buffering system in the human body. Up to ¾ of the carbon dioxide in the human body is converted to carbonic acid which is quickly turned to bicarbonate. Bicarbonate is an alkali so helps to keep the acid-base balance of the body stable.
Debbie
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Neutralization of tumor acidity improves anti-tumor responses to immunotherapies
Cont…
Introduction
The amplitude and quality of T cell activation in response to antigen activation of the T cell receptor (TCR) is tightly controlled by engagement of inhibitory receptors, such as PD-1, Lag-3, Tim-3, BTLA and CTLA4. The ability of tumors to co-opt these inhibitory pathways plays an important role in the inhibition of T cell responses within the tumor microenvironment (1,2). Treatment with fully humanized neutralizing monoclonal antibodies against CTLA4, PD-1 or its ligand PD-L1, has led to durable anti-tumor responses where conventional therapies have failed (3–5). However, response rates remain low, from 18–27% for anti-PD-1 antibodies (6), and 11% for anti-CTLA4 antibodies (7). Recent studies have shown that multiple checkpoints can be co-expressed on individual TILs, such as PD-1+TIM-3+ T cells which are defective in proliferation and cytokine production (8–10). Indeed, a recent clinical trial combined PD-1 and CTLA4 blockade in patients with melanoma, and showed an increase rate of objective tumor responses as compared with blocking either checkpoint alone, 40% vs. 20% (11). However, there remain a significant proportion of non-responders, suggesting that additional immunosuppressive pathways are active.
Regulatory T cells (Tregs) or myeloid derived suppressors cells (MDSC) are also known to blunt T cell responses (12,13). Tregs suppress antigen-specific T cell response and removal of Tregs in murine models led to enhanced anti-tumor T cell responses and tumor rejection (14). MDSCs are comprised of immature macrophages, granulocytes and dendritic cells, DC (15). They suppress T cell responses, reduce antigen specific CD8+ T cell proliferation, increase T cell death by apoptosis (16), and their elimination has been shown to enhance anti-tumor immunity and tumor regression in murine tumor models (17). In addition to these cell-based inhibitors of immune function, there are also secreted factors that block T cell activation. The most widely studied of these are the kyenuranines, which are synthesized by the tryptophan-metabolizing enzyme, indoleamine-2,3-dioxygenase, IDO. IDO can be expressed by cancer cells and is normally expressed by DCs in response to Interferon-γ (IFN-γ) in order to blunt immune activation (18). There has also been evidence that tumor derived acidity also plays a role in immune-suppression (19).
Solid tumors are unequivocally acidic (20). This is commonly believed to be a consequence of high rates of fermentative metabolism in a poorly perfused environment (21). However, newer models point to an active role for the membrane bound carbonic anhydrase IX (CAIX) in establishing extracellular acidity (22). This is relevant, as CAIX is an independent negative prognostic indicator in a number of cancers including, inter alia, breast (23), lung (24), and ovarian (25) cancers. Tumor acidity is important to tumor progression, as it has been shown to promote local invasion and metastasis (26), and metastasis can be inhibited by neutralization of acidity with oral buffers (27,28).
Tumor-derived acidity is also hypothesized to suppress immune function (19). For example, lactic acidosis is a strong negative prognostic indicator in sepsis (29). In vitro, acidic pH (6.5) can suppress T cell functions, including IL-2 secretion and activation of T cell receptors (30), although the mechanism by which this occurs is not known. Likewise, there is evidence that acid pH affects other components of the immune systems, such as dendritic cells (DCs), MDSCs or macrophages, yet these effects are also not known with certainty (19). For example, inhibition of proton pumps on tumor cells with omeprazoles can hamper tumor-induced suppression of macrophages in vitro & in vivo (31,32), yet this activity may be due to off-target effects, as the target for these drugs are not known to be expressed in the immune system. It may be assumed that the effects of acidity are not mediated via acidification of the intracellular pH (pHi), as the pHi has been shown to be highly buffered in activated T cells (33). More recently, families of specific acid-sensing receptors have been identified (34) and shown to transduce extracellular acidity into intracellular signals. For example, acid pH has been shown to activate the G-protein, T cell inhibitory receptor, TDAG8 (T cell death-associated gene-8) (35), and this has been shown to be responsible for a reduction in c-myc translation in lymphocytes (36). In this study, we examined the effect of tumor acidity on anti-tumor immunotherapeutic strategies and observed that neutralization of tumor pH with bicarbonate increases response to checkpoint inhibitors and, importantly, led to cures in combination with adoptive T cell therapy.
Cont…
Introduction
The amplitude and quality of T cell activation in response to antigen activation of the T cell receptor (TCR) is tightly controlled by engagement of inhibitory receptors, such as PD-1, Lag-3, Tim-3, BTLA and CTLA4. The ability of tumors to co-opt these inhibitory pathways plays an important role in the inhibition of T cell responses within the tumor microenvironment (1,2). Treatment with fully humanized neutralizing monoclonal antibodies against CTLA4, PD-1 or its ligand PD-L1, has led to durable anti-tumor responses where conventional therapies have failed (3–5). However, response rates remain low, from 18–27% for anti-PD-1 antibodies (6), and 11% for anti-CTLA4 antibodies (7). Recent studies have shown that multiple checkpoints can be co-expressed on individual TILs, such as PD-1+TIM-3+ T cells which are defective in proliferation and cytokine production (8–10). Indeed, a recent clinical trial combined PD-1 and CTLA4 blockade in patients with melanoma, and showed an increase rate of objective tumor responses as compared with blocking either checkpoint alone, 40% vs. 20% (11). However, there remain a significant proportion of non-responders, suggesting that additional immunosuppressive pathways are active.
Regulatory T cells (Tregs) or myeloid derived suppressors cells (MDSC) are also known to blunt T cell responses (12,13). Tregs suppress antigen-specific T cell response and removal of Tregs in murine models led to enhanced anti-tumor T cell responses and tumor rejection (14). MDSCs are comprised of immature macrophages, granulocytes and dendritic cells, DC (15). They suppress T cell responses, reduce antigen specific CD8+ T cell proliferation, increase T cell death by apoptosis (16), and their elimination has been shown to enhance anti-tumor immunity and tumor regression in murine tumor models (17). In addition to these cell-based inhibitors of immune function, there are also secreted factors that block T cell activation. The most widely studied of these are the kyenuranines, which are synthesized by the tryptophan-metabolizing enzyme, indoleamine-2,3-dioxygenase, IDO. IDO can be expressed by cancer cells and is normally expressed by DCs in response to Interferon-γ (IFN-γ) in order to blunt immune activation (18). There has also been evidence that tumor derived acidity also plays a role in immune-suppression (19).
Solid tumors are unequivocally acidic (20). This is commonly believed to be a consequence of high rates of fermentative metabolism in a poorly perfused environment (21). However, newer models point to an active role for the membrane bound carbonic anhydrase IX (CAIX) in establishing extracellular acidity (22). This is relevant, as CAIX is an independent negative prognostic indicator in a number of cancers including, inter alia, breast (23), lung (24), and ovarian (25) cancers. Tumor acidity is important to tumor progression, as it has been shown to promote local invasion and metastasis (26), and metastasis can be inhibited by neutralization of acidity with oral buffers (27,28).
Tumor-derived acidity is also hypothesized to suppress immune function (19). For example, lactic acidosis is a strong negative prognostic indicator in sepsis (29). In vitro, acidic pH (6.5) can suppress T cell functions, including IL-2 secretion and activation of T cell receptors (30), although the mechanism by which this occurs is not known. Likewise, there is evidence that acid pH affects other components of the immune systems, such as dendritic cells (DCs), MDSCs or macrophages, yet these effects are also not known with certainty (19). For example, inhibition of proton pumps on tumor cells with omeprazoles can hamper tumor-induced suppression of macrophages in vitro & in vivo (31,32), yet this activity may be due to off-target effects, as the target for these drugs are not known to be expressed in the immune system. It may be assumed that the effects of acidity are not mediated via acidification of the intracellular pH (pHi), as the pHi has been shown to be highly buffered in activated T cells (33). More recently, families of specific acid-sensing receptors have been identified (34) and shown to transduce extracellular acidity into intracellular signals. For example, acid pH has been shown to activate the G-protein, T cell inhibitory receptor, TDAG8 (T cell death-associated gene-8) (35), and this has been shown to be responsible for a reduction in c-myc translation in lymphocytes (36). In this study, we examined the effect of tumor acidity on anti-tumor immunotherapeutic strategies and observed that neutralization of tumor pH with bicarbonate increases response to checkpoint inhibitors and, importantly, led to cures in combination with adoptive T cell therapy.
Debbie
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Thanks, Debbie, for an interesting read. So, is there maybe benefit in dropping some sodium bicarbonate in water to neutralize ph?
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
Hi Miranda ,
It’s definitely a topic to visit with your team about .😊
There are a whole lot of ways to create a better alkaline environment so as to create an healthier immune system bases.
https://www.verywellhealth.com/baking-s ... er-5086575
Each patient is different and requires different restrictions, before embarking on this regiment , a person should always always talk with their doctors
ASPS is certainly a rare sarcoma that needs a healthy immune system or it will progress, as will most cancers .
Ps I’d personally be more concerned about possible electrolyte and then possible metabolic imbalances?
It’s definitely a topic to visit with your team about .😊
There are a whole lot of ways to create a better alkaline environment so as to create an healthier immune system bases.
https://www.verywellhealth.com/baking-s ... er-5086575
Each patient is different and requires different restrictions, before embarking on this regiment , a person should always always talk with their doctors
ASPS is certainly a rare sarcoma that needs a healthy immune system or it will progress, as will most cancers .
Ps I’d personally be more concerned about possible electrolyte and then possible metabolic imbalances?
Debbie
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
The article is about the neutralization of tumor acidity not the body acidity. I personally have no idea how to lower the intra-tumor acidity.
Olga
Re: Lactate in Sarcoma Microenvironment: Much More than just a Waste Product
The tumor microenvironment is acidic due to glycolytic cancer cell metabolism, hypoxia, and deficient blood perfusion. It is proposed that acidosis in the tumor microenvironment is an important stress factor and selection force for cancer cell somatic
Debbie
Causes, Consequences, and Therapy of Tumors Acidosis
Causes, Consequences, and Therapy of Tumors Abstract
While cancer is commonly described as “a disease of the genes”, it is also associated with massive metabolic re-programming that is now accepted as a disease “Hallmark”. This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect”. Much has been written about the mechanisms of the Warburg effect and this remains a topic of great debate. However, herein we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: 1) neutralizing acid directly with buffers; 2) targeting metabolic vulnerabilities revealed by acidosis, 3) development of acid-activatable drugs and nanomedicines, and 4) inhibiting metabolic processes responsible for generating acids in the first place.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625890/
While cancer is commonly described as “a disease of the genes”, it is also associated with massive metabolic re-programming that is now accepted as a disease “Hallmark”. This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect”. Much has been written about the mechanisms of the Warburg effect and this remains a topic of great debate. However, herein we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: 1) neutralizing acid directly with buffers; 2) targeting metabolic vulnerabilities revealed by acidosis, 3) development of acid-activatable drugs and nanomedicines, and 4) inhibiting metabolic processes responsible for generating acids in the first place.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625890/
Debbie