Other strategies have been pursed to target TNF to the tumor. As an example, TNF has been fused with the single chain Fv Ab L19, which is specific for the extradomain B of fibronectin expressed by the tumor neovasculature However, the location of the target molecules in tumor vessels and their level of expression are different from that of CD13, and additional studies are necessary to investigate whether this compound acts in synergy with active or adoptive immunotherapy.
Leukocyte infiltration in tumors can also be favored by the use of classic anti-angiogenic drugs. VEGF is the focus of most of these approaches This was reported to be one of the strongest prognostic factors in ovarian carcinoma In addition, VEGF negatively regulates functional maturation of and antigen presentation by dendritic cells DCs , favors the accrual and activity of cell populations with immunosuppressive functions including myeloid derived suppressor cells [MDSCs; 57 ] and regulatory T cells [Tregs; 58 ], and induces T cell apoptosis, therefore contributing to the immunosuppressive tumor microenvironment Over the last decades several therapeutic approaches have been proposed to counteract VEGF and neoangiogenesis, such as anti-VEGF antibodies and tyrosine kinase inhibitors of multiple pro-angiogenic growth factor receptors Anti-angiogenic drugs transiently normalize the tumor-vasculature, pruning away immature and leaky vessels and remodeling the remaining vasculature.
As a result, the enhanced oncotic pressure gradient together with decreased interstitial fluid pressure and hydrostatic pressure gradient facilitate delivery of oxygen, nutrients, and also chemotherapeutic agents into the tumor microenvironment Some of these strategies can also overcome EC anergy and promote leukocyte infiltration in tumors [Figure 2 C; 60 — 62 ].
Impaired lymphocyte trafficking in mice deficient in the kinase activity of PKN1
Thus, anti-angiogenic drugs and TNF targeting are conceptually different approaches, as the former aims at vessel normalization, whereas the latter exploits the cytokine as an inflammatory agent that induces vascular activation. Because of the extensive tumor necrosis induced by the adoptive transfer of T cells, vessels could not be investigated in these tumors In general, anti-VEGF-mediated transient normalization of tumor vessels lasts between few days to a month Unfortunately, the anti-angiogenic drugs available to date are not sufficiently selective in damaging only neo-angiogenic vessels.
The latter effect may be dangerous also for highly vascularized tissues, including the cardiovascular, endocrine, and nervous systems As mentioned before, targeting TNF to the tumor vessels enhances tumor permeability to chemotherapeutic agents We have recently reported that the combination of active or adoptive immunotherapy, vascular targeting, and chemotherapy act in synergy against melanoma Our preliminary results also suggest that in the context of adoptive T cell therapy after hematopoietic stem cell transplantation 70 , 71 , NGR-TNF dramatically increases the infiltration of TILs into the prostate of mice affected by autochthonous prostate cancer 49 and contributes to tumor debulking Mondino A.
Personal communication. Interestingly, chemotherapeutic agents, beside their effects in promoting anti-tumor immunity by inducing a more immunogenic death of cancer cells, increasing their sensitivity to immune effectors or depleting the tumor microenvironment of Treg cells and MDSCs 72 , 73 have been shown to promote intratumor expression of chemokines attracting T cells Taken together, these findings support the concept that increasing T-cell traffic to the tumor, possibly in association with immunogenic chemotherapy, may be a valid strategy to enhance response to immunotherapy in cancer patients.
Reprograming energy metabolism is an emerging hallmark of cancer closely linked to hypoxia and neoangiogenesis Indeed, uncontrolled cell proliferation requires a continuous adjustment of energy metabolism in order to fuel cell growth and division also in the absence of adequate tumor perfusion As summarized in Figure 3 , a direct consequence of aerobic glycolysis is the production of lactate from pyruvate, and acidic metabolites that cause drop in extracellular pH 78 , which may select for more aggressive acid-resistant clones and favor tumor invasion A low extracellular pH triggers the activation on tumor cell membranes of transporters that protect the cytosol from acidosis.
In addition, hypoxia stabilizes the heterodimer HIF-1, which in turn induces the up-regulation of glucose transporters and CA-IX, thereby increasing acidity within the tumor microenvironment As a result, while in normal tissues the extracellular pH is maintained around 7. Figure 3. Metabolic alterations within the tumor microenvironment. The cartoon summarizes the metabolic alterations often found within the tumor microenvironment that may impact on T cell fitness. See the text for more details. Hypoxia and pH are also strongly tangled with reduction-oxidation redox reactions Figure 3.
Already at the earliest stages of tumor development, free radicals, HIFinduced gene expression and hypoxia are strictly interconnected Indeed, reactive oxygen species ROS are generated in mitochondria of cells exposed to low oxygen 84 , and the phenomenon is further amplified by cyclic reoxygenation. Also the anti-oxidant systems upregulated by tumor cells to counterbalance oxidative stress contribute to the altered redox of the tumor microenvironment and to tumor progression.
Overexpression of reducing enzymes such as thioredoxin TRX has been found in many tumors and correlated to poor prognosis 85 , In addition, proton pumps have been proposed to de-toxify tumor cells from microenvironmental ROS Thus, hypoxia, acidosis, redox-remodeling can cooperate to establish a more aggressive malignant phenotype, and possibly to promote the derangement of immune functions The immune system has been proposed as sensor of the metabolic state Bidirectional communication and coordination between metabolism and immunity, while effective in maintaining and defending the internal environment from the environment around us, may result in inhibition of immune functions and may favor chronic inflammation and cancer.
A well-known example of metabolism-mediated limitation of the function and survival of TILs is tryptophan consumption by tumor cells and antigen presenting cells APCs producing IDO More specifically, hypoxia, acidosis, and redox-remodeling are all perceived as sensors by the immune system. Thus, as summarized in Table 1 , hypoxia inhibits TCR-triggered signaling, proliferation and cytokine production by T cells 92 , T cells are also inhibited by hypoxia-driven accumulation of extracellular adenosine More recently it has been reported that hypoxia within the tumor microenvironment promotes Treg recruitment through the induction of CC-chemokine ligand 28 Th17 cells are a subpopulation of T helper cells producing IL17, IL17F, and IL22, which play a critical role in immunity to certain pathogens and autoimmune inflammation The role of Th17 cells in cancer is more debated.
Indeed, Th17 exert anti-tumorigenic activities, likely by facilitating the recruitment of other effector immune cells , and pro-tumorigenic activities by inducing tumor vascularization and the release of tumor-promoting factors by tumor and stromal cells Thus, the effects of hypoxia on the tumor microenvironment are rather complex, and the use of HIF inhibitors for therapeutic purposes should be carefully balanced to avoid the dominance of pro-tumorigenic over anti-tumorigenic mechanisms.
It remains to be defined how coordinated silencing of these three genes affects cancer cell susceptibility to CTL lysis. The effect of hypoxia on CTLs is still debated Interestingly, simultaneous glucose deprivation and hypoxia block T cell-mediated cytotoxicity in vitro , therefore suggesting an additional mechanism of immunosuppression within the tumor microenvironment.
There are relatively few reports on the impact of low intratumor pH on T cells Clinical evidence suggests that metabolic acidosis is often associated with immunodeficiency Indeed, both leukocyte activation and the bactericidal capacity of leukocytes are generally impaired at reduced pH suggesting that T cells could be extremely sensitive to pH variations. Lymphocytes also die at the same acidic pH malignant tumor cells perfectly remain alive Droge et al. Few years later, it was reported that the proliferation of ILstimulated T cells is inhibited at pH 6.
More recently, Fischer and colleagues demonstrated that high lactic acid concentrations, as the ones found in the tumor environment, block lactic acid export in human T cells, thereby disturbing proliferation and effector functions We have found that lowering the pH in vitro to values most frequently detected within tumors pH 6—6. Interestingly, buffering of culture pH to physiologic values associates with the complete recovery of T cell functions, although longer exposure or lower pH values causes permanent damage and T cell death , arguing that a portion of T cell immunity might be lost at tumor site when extreme metabolic alterations are present.
Interestingly, similar characteristics were found in tumor-specific CTLs infiltrating melanoma lesions, whose pH was 6. Thus, acidity per se is a novel tumor cell extrinsic mechanism of immune escape Whereas redox-activated signaling events are physiologically needed both as antimicrobial defense and to guarantee the correct spatial and temporal extension of the immune reaction, redox-remodeling within the tumor microenvironment negatively affects immune surveillance. Indeed, oxygen ions and peroxides are potent antibacterial agents produced by phagocytic cells including macrophages and neutrophils It has also been increasingly appreciated that endogenous ROS are required for optimal T cell activation Yet, exogenous oxidative stress may dramatically suppress T cell activation and effector functions.
As an example, macrophages within the tumor microenvironment express inducible nitric oxide synthase iNOS and can induce tumor killing by generating large amounts of nitric oxide NO. However, iNOS is also expressed by MDSCs, a heterogeneous population of cells of myeloid origin that include immature macrophages, granulocytes, DCs and other myeloid cells MDSCs also express arginase 1 Arg1 that together with iNOS metabolizes the essential aminoacid arginine to either l -ornithine and urea, or to l -citrulline and NO , Nitration of chemokines also prevents intratumoral infiltration of antigen-specific T cells Also Tregs modulate the redox of the microenvironment by subtracting cysteine necessary to effector T cell, function Indeed, DCs within the tumor microenvironment may have additional nutritional and redox-remodeling roles, since they reduce the extracellular microenvironment required for T cell activation by releasing cysteine and TRX In the same vein, Tregs diminish glutathione synthesis in DCs and consume extracellular cysteine , thus remodeling extracellular redox.
Additional hypoxia-driven metabolic dysfunctions, leading to the accumulation of extracellular adenosine, further increased by Tregs , , could act in synergy with acidic pH in dampening T cell function through A2A adenosine receptor-driven cAMP intracellular accumulation All together these findings sustain the concept that hypoxia, nutrient deprivation, abnormal glycolysis, and low pH act in synergy crippling immune surveillance Figure 1. Also alterations of the lipid metabolism that occur in the tumor microenvironment might affect T cell functions [e. Different therapeutic approaches have been proposed to modulate hypoxia, tumor acidity or redox, which directly or indirectly affect TIL viability and effector functions Figure 1.
Being the tumor microenvironment so complex and redundant, the risk remains that interfering with one metabolic pathway, thus inhibiting one pro-tumoral mechanism, may favor another. For the sake of brevity, we will touch upon some clarifying examples. It has been reported that the anti-VEGF monoclonal antibody bevacizumab induces intratumoral hypoxia, likely through excessive vessel remodeling , thus increasing the population of cancer stem cells CSCs in human breast cancer xenografts , and promoting epithelial to mesenchymal transition EMT in a murine model of bevacizumab-resistant pancreatic cancer Angiogenesis inhibitors targeting the VEGF pathway may also elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis Bevacizumab has also been shown to induce malignant traits through induction of paracrine factors, which recruited pro-angiogenic myeloid cells , whose phenotype is reminiscent of MDSCs.
Thus, anti-angiogenic compounds while cutting nutritional support to tumor cells, may favor local hypoxia and MDSC accumulation. Also sunitinib, a receptor tyrosine kinase inhibitor with anti-angiogenic properties , which has been recently approved for the treatment of metastatic renal cell carcinoma , induces hypoxia, through a yet undefined mechanism, and increase in CSCs Interestingly, semaphoring 3A Sema3A , an endogenous anti-angiogenic agent, counteracts sunitinib-induced tumor hypoxia, and Sema3A and sunitinib synergize to enhance survival of tumor-bearing mice In addition, one cycle of treatment with sunitinib is sufficient to increase the proportion of type 1 T cells , likely by reducing MDSCs These findings have been confirmed in mouse models of cancer, in which sunitinib reduced viability and proliferation of MDSCs and their accumulation in tumors However, HIF-1 inhibitors may impact on balance between Treg and Th17 cells favoring the former 99 , Thus, further investigation is needed to fully elucidate the therapeutic potential of HIF-1 inhibitors in cancer patients.
Conversely, hypoxia can be skillfully utilized to selectively target TILs. Indeed, hypoxia induces expression of CD BB on TILs, and low-dose intratumoral injections of agonist anti-CD monoclonal antibodies avoid systemic toxicity while achieving anti-tumor systemic effects Several strategies have been proposed to neutralize intratumor acidity and therefore affect TILs. Robey et al.
However, no information is available on the effects of systemic administration of bicarbonate on T cells and there is some concern related to the risk of metabolic alkalosis. We obtained evidence that systemic administration of the PPI esomeprazole PPIs also affected adoptively transferred T cells that reached the tumor, and PPI treatment increased the therapeutic potential of both active and adoptive immunotherapies Because of the high selectivity for an acidic milieu and instability, PPIs can be safely used at high doses as the one tested by us , which also affect tumor cells in vivo Thus, PPI treatment may represent a promising strategy for recovering specific immunity and improving the efficacy of T cell-based cancer treatments.
PPIs are also known for their anti-oxidant and anti-inflammatory activities Vacuolar proton pumps are expressed in the membrane of phagolysosomes of neutrophils, and lysosomal acidification is relevant for neutrophil oxidative burst. Whiles the mechanism of action of PPIs on leukocytes is still under investigation , our data suggest that in vivo PPIs enhance anti-tumor activities of TILs , Cancer cells promote chronic autophagy as survival adaptation to the acidic microenvironment Because at least in vitro autophagy can also be induced in tumor cells by PPIs , strategies might be devised to inhibit autophagy during PPI treatment, yet taking into account the potentially negative effects of autophagy inhibitors on TILs Regarding redox, it has been reported that the anti-diabetic drug metformin or the mTOR inhibitor rapamycin, restore catabolic mitochondrial fatty acid oxidation and favor the induction of memory T cells, thus increasing the therapeutic efficacy of cancer vaccines , , Several pre-clinical studies also support the use of A2A adenosine receptors A2ARs antagonists to increase T cell activity within the tumor microenvironment As an example, the compounds ZM or 1,3,7-trimethylxanthine caffeine showed to increase the anti-tumor activity of adoptively transferred T cells in mice bearing large tumors Curiously, drinking coffee was found to correlate with significant decreased risk of cutaneous malignant melanoma only in women , , suggesting that caffeine may also impact on cancer immune surveillance.
Finally, therapeutic strategies targeting either Tregs , or MDSCs , ; , , collaborate in making the tumor microenvironment more permissive for TIL survival and anti-tumor activities. Thus, therapeutic strategies that block MDSCs accrual at the tumor site and their immunosuppressive function, and more specifically drugs interfering with chemokine nitration, are expected to significantly improve the efficacy of both active and adoptive immunotherapies. Despite considerable progress over the last decade, the tumor microenvironment is an area of research that remains ripe for further investigation, especially with regard to the relentless and dynamic modifications in its cellular composition and metabolism.
Accumulating experimental evidence lends weight to the concept that the most effective therapeutic strategies against cancer will be the ones that consider the tumor and its microenvironment as a whole, and yet simultaneously and coordinately address several individual aspects of this complex system. A step forward will be to carefully devise multiple targeted therapies that simultaneously or subsequently attack tumor cells and the diverse aspects of the tumor microenvironment, and yet preserve the function of organs not involved by the neoplasm.
As an example, in TRAMP mice affected by advanced prostate cancer, the combination of non-myeloablative total body irradiation, hematopoietic stem cell transplantation, infusion of donor mature lymphocytes, and tumor-specific vaccination overcomes tumor-specific T cell tolerance, prompts tumor debulking, and induces long-lasting tumor-specific memory response that protects mice from tumor recurrence Interestingly, the addition of NGR-TNF at the peak of the vaccination-induced immune response favors penetration of activated T cells within the transformed prostate epithelium 49 and guarantees an even stronger anti-tumor activity Mondino A.
We are investigating the possibility to add PPIs to this already complex combined therapy to favor the anti-tumor activity of adoptively transferred and vaccine-induced T cells that have reached the prostate. Given the outstanding results obtained with immune checkpoint blockers in cancer patients , it will be particularly interesting to investigate the therapeutic efficacy of their combination with metabolism and vessel modulators.
It is also important to underline that more is not always better One example is the recent failure of a well-designed and carefully analyzed multi-institutional clinical trial in which patients with previously untreated metastatic colorectal cancer were randomly assigned to receive the combination of capecitabine, oxaliplatin, and bevacizumab i. The four-drug combination resulted in significantly shorter progression-free survival and inferior quality of life.
A similarly negative effect was obtained when another anti-EGFR monoclonal antibody i. Thus, additional investigation is needed to define the best settings for each combination approach. In this perspective, reliable animal models of human diseases remain instrumental. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Advance article alerts. Article activity alert. Receive exclusive offers and updates from Oxford Academic. More on this topic The ABO, Lewis and related blood group antigens; a review of structure and biosynthesis. Toward this aim, it has been shown in a mouse model that M2 macrophages infiltration required CCR2 ligand expression in tumors Chemokine receptors are also expressed by melanoma cells allowing them to disseminate elsewhere in the organism, preferentially in the draining lymph nodes, lung, liver, gut, and brain where they form secondary lesions , Lymphocyte trafficking to and within the skin is a highly regulated process involving unique and complex combinations of adhesion molecules and chemokine receptors Figure 2.
These combinations are cell-specific thereby controlling the type and location of the recruited cells. Lymphocytes are effectively recruited in inflamed tumors, but they are inhibited by immunomodulatory mechanisms Exhaustion, Treg infiltration. However, they poorly infiltrate non-inflamed tumors. Mimicking strategies induced by an inflammatory context has shown some successes in cancer. Indeed, the upregulation of adhesion molecules and chemokines on tumor vessels induced by the selective delivery of TNF NGR-TNF to these vessels has shown to increase the recruitment of endogenous or adoptively transferred T cells Indeed, similar to that recently performed in breast cancer, single cell RNAseq analysis of melanoma TILs could yield valuable insights into the precise guidance cues required for cutaneous tumor entry Further, there are still gaps in knowledge of the prognostic value in identifying distinct populations within melanoma or how individual lymphocyte populations are altered by interventions such as checkpoint inhibition.
In addition, we still fail to fully understand how innate and adaptive lymphocytes work together to influence cancer growth. Recently, NK cells were highlighted as major orchestrators of cDC1 recruitment into melanomas; an axis that provides promising potential However, the role that innate lymphocytes play in the co-ordination of TIL recruitment and function is under studied.
We believe that a better understanding of lymphocyte specific location and interacting partners would help future successes in melanoma treatment. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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