The Oncogenic Landscape of the Idiopathic Pulmonary Fibrosis: A Narrative Review

Giulia Maria Stella; Vito D'Agnano; Davide Piloni; Laura Saracino; Sara Lettieri; Francesca Mariani; Andrea Lancia; Chandra Bortolotto; Pietro Rinaldi; Francesco Falanga; Cristiano Primiceri; Angelo Guido Corsico; Andrea Bianco

Disclosures

Transl Lung Cancer Res. 2022;11(3):472-496. 

In This Article

A Perspective on Novel Cancer-related Therapies in IPF

Rationale for Immunotherapy in Fibrotic Lung

It is well known that inflammation plays a relevant pathogenic role in IPF even though anti-inflammatory drugs as steroids do not impact significantly on disease progression.[209] This observation points out that the role on inflammatory reactions might not be a driver of IPF, or more properly, the complex IPF context requires a deeper characterization of the inflammatory pathways involved to identify effective targets. The inflammatory profile of IPF is characterized by type 2 inflammation[210,211] involving the interleukin (IL)-13 and IL-4, produced by T helper 2 (Th2) cells and type 2 innate lymphocytes; both are suggested to play a prominent role in fibrosis development.[212] Type 2 immune cascade is known to drive pathogenic events in allergic asthma and several inhibitory molecules have reached the clinical use. Among them anti IL-13 monoclonal antibody (mAb) lebrikizumab has been recently tested in the randomized, multicenter, double-blind, placebo-controlled, parallel-group study NCT01872689 trial aimed at evaluating its efficacy and safety as monotherapy or with pirfenidone in IPF subjects. Although the pharmacodynamic biomarkers indicated a certain activity of lebrikizumab in association to the already known safety profile, lebrikizumab alone or in combination with pirfenidone showed no additional advantages since it was not able to improve functional parameters.[213] Similar results have been reported using the anti-IL-13 mAb tralokinumab which safety profile resulted acceptable in absence of significant advantages (NCT01629667, NCT02036580)[214] and the study evaluating the mAb dectrekumab in IPF was discontinued in absence of significant results.[215] These observations suggest that IL-13/type 2 immunity might not be the right target in IPF onset although a potential role of type 2-driven immune response is conceivable in acute exacerbation (AE) of disease. Growing evidence point out that many important fibrogenic steps should be orchestrated by both innate and adaptive immunity and that the innate response prevails[216] or, more properly, that the epithelial damage plays an important role in inducing immune system dysregulation which acts as critical driver for disease progression.[217] This specific feature is a common denominator to cancer[218–220] and sustain a rationale for IC blockade therapeutic strategy. Immunotherapy has substantially changed the therapeutic strategies for cancers such as melanomas, lymphomas, and lung tumors. Unfortunately, only 20–50% of patients with advanced solid tumors respond to treatment. There is therefore a need for the development of methods to identify patients who are most likely to respond to immunotherapy. ICs are molecules located on the surface of cells that can send inhibitory stimuli to attenuate immune responses. Tumors express IC proteins on their cell surface to escape detection from the immune system. Thus, targeted inhibition towards these receptors enhances T cell response against the tumor. Tumor cells express checkpoint proteins on their surface to evade host immune response. Targeted inhibition towards these receptors enhances T cell response towards the tumor.[221,222] Cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-1, and PD-L1 are key negative regulators of anti-tumor T cell reactivity. The development of IC inhibitors has revolutionized the treatment of a variety of cancers. Several studies have shown that pre-existing tumoral and peritumoral immune infiltration correlates with patient response to PD-1 and PD-L1 immunotherapy. Three distinct immune phenotypes have been described: immune-inflamed, immune-excluded, and immune-desert. Immune-inflamed tumors are characterized by dense, functional CD8 cell infiltration, increased interferon-γ signaling, expression of cell checkpoint markers (such as PD-L1), and a high mutational burden. These tumors tend to respond to immunotherapy. The detailed description of cancer microenvironment and sensitivity to IC inhibitors (ICIs) goes beyond the scope of this paper. It should be underlined that the cellular heterogeneity which characterizes IPF complicates data interpretation and can make elusive data interpretation when obtained from tissue homogenates. The recently completed study entitled "Immunopathologic Profiles and Blood Biomarkers in Patients With IPF" (NCT04187079) aimed at IPF tissue and blood profiling also investigating the cellular expression of ICs (namely PD-L1) in lung epithelial cells. It is known that PD1-PDL1 are expressed in IPF lymphocytes,[223] AMs[224] and myofibroblasts[159] through IHC stain and RNA sequencing. The PD-1/PD-L1 axis is likely to contribute to lung fibrogenesis[225] anti PD-L1 Abs significantly reduces pulmonary fibrosis.[226] PD-1 expression on CD4+ T cells is known to lead to activation of Signal Transducer and Activator of Transcription (STAT) 3 which, in turn, induces IL-17A and TGF-β expression.[227]Ex vivo blockade of the PD-1/PD-L1 axis is associated to STAT3-mediated IL-17A and TGF-β production by CD4+ T cells.[223] PD-L1 inhibitors should not be used in conjunction with mesenchymal stromal cell (MSC) therapy.[228] CTLA-4 is strongly overexpressed in IPF CD4- and CD28 null IPF lymphocytes if compared to health cells and anti-CTLA-4 antibody treatment was shown to aggravate fibrosis in a humanized IPF model.[173,225,229] Notably, a high level of hypoxia and immune activity is associated to worst prognosis in IPF, whereas those patients featuring high level of oxygen and low immunogenic reactions the best prognosis.[230] These preliminary findings point out a novel strategy to effectively select patients for immunotherapy. Overall, the expression of IC molecules in lung fibrotic tissues sustain a rationale for a deeper investigation of their pathogenic role and as actionable targets. Durable responses to nivolumab in a lung cancer patient withs idiopathic pulmonary fibrosis.[231–233] This observation suggests that in those cases, ICI treatment should be considered a potentially effective option even though the occurrence of ILD has been identified as a rare but potentially severe event induced by immunotherapy.[234] In this perspective the already reported activation of the MET oncogene in IPF should become relevant.[9] IPF resembles cancer in two critical MET-associated behaviors: invasive phenotype and pro-coagulant status. In cancer, MET activation occurs as a late event, consequently to transcriptional up-regulation driven by unfavorable microenvironmental conditions MET (mainly hypoxia) amplified cancer clones are selected under therapeutic pressure in a context of molecularly heterogeneous lesions exposed to targeted therapies or radiotherapy.[235,236] Thus, this oncogenic expedient[69] can be exploited for therapeutic purposes in IPF. Moreover, it has been already reported that, in lung cancer mutations occurring in several oncogenes among which MET, modulate tumor microenvironment and a positive correlation between MET amplification and PDL1 overexpression has been already reported.[237,238] Thus, in a context-specific regulation of its expression, MET might become a functional marker of IPF and an actionable target, positively associated to response to ICIs (Figure 2).

Figure 2.

Functional annotation of the MET oncogene as an actionable target of IPF. MET-mediated events in IPF rely on qualitative differences among physiological signals. No driver genetic lesions, causally implicated in the disease can be clearly demonstrated ("Fibrogenic Expedience"). The MET blockage falls among those therapeutic strategies aimed at impairing the "aberrant recapitulation of developmental programs". The hypoxia-induced MET up-regulation might cooperate in triggering IPF regenerative/reparative processes. HGF, hepatocyte growth factor; IPF, idiopathic pulmonary fibrosis.

Radiotherapy in Lung Cancer With IPF

Radiation induced lung injury (RILI) represents one of the major issues in the setting of thoracic radiotherapy;[239] it generally corresponds to radiation-induced pneumonitis, an intermediate phase injury after exposure to ionising irradiation, which in most cases paves the way for the development of late fibrosis. Both pneumonitis and fibrosis are dose-limiting toxicities of great concern to the radiation oncologist, especially in the scenario of a combined chemoradiotherapy approach or in high dose hypo-fractionated radiotherapy.

Thoracic radiotherapy plays a role in enhancing the occurrence of AEs in IPF, even when baseline symptoms are trivial. Pre-existing IPF is a well-known risk factor for pulmonary toxicity after ionising irradiation;[240] previous reports have shown that it can raise the risk of severe and even life-threatening pneumonitis, whose rates in such patients range between 6.3% and 18.2%, in relation to different radiotherapy techniques.[241] Nevertheless, IPF does not constitute an absolute contraindication for thoracic radiotherapy, even if European Organisation for Research and Treatment of Cancer (EORTC) guidelines suggest avoiding irradiating lung cancer patients with IPF.[242] While some encouraging data come from some preliminary experiences with proton therapy,[241] the decision to offer radiotherapy to these patients should be made after a multidisciplinary approach in which patient's individual risk is evaluated, especially in terms of his/her clinical status, disease specific survival and therapeutic index.

Surgery in Lung Cancer With IPF

Lung resection plays a role in the treatment of patients affected by IPF with resectable NSCLC. However, in this scenario, two major issues influence significantly the surgical procedure and the survival outcomes: the high risk of postoperative AEs of IPF in the short-term, and the death due to cancer in the long-term.[243] Surgery is a defined risk factor for AE in IPF patients[16] and since its incidence in this group of patients is estimated to be approximately 9.3%[244] and no preventive measure is known, it is crucial to carefully select the patients to properly refer treat the patients. In a study by T. Sato and colleagues, a simple scoring system to identify high risk patients for AE was derived in order to help in the decision-making process for surgery selection and predict the patients requiring intensive observation postoperatively.[245] Among the surgical procedures of lung resection, wedge resection is associated to the lowest risks of postoperative AE compared to segmentectomy, lobectomy, bilobectomy and pneumonectomy, since AE risk increases according to the resected lung parenchyma volume.[244] Death due to cancer is the major concern in the long-term: it represents the main cause of death in lung cancer patients affected by IPF, mostly attributable to cancer recurrence after surgery. Contrary to AE risk, lobectomy shows better results for death due to cancer in patients with stage IA, while wedge resection and segmentectomy were associated to poor outcomes.[244]

Lung resection in patients with IPF is challenging but required for several patients. The choice of surgical procedure must be tailored based on several criteria, such as pulmonary function, cancer stage and recurrence risk, postoperative AE risk, and the natural course of IPF.

Percutaneous Thermal Ablation in Lung Cancer With IPF

Alternative treatments such as radiofrequency ablation could be of therapeutic benefit with relatively minimal complications, particularly in patients who are not fit enough for surgical interventions. On the other hand, the risk of severe complications with stereotactic body radiation therapy (SBRT) when treating patients with IPF is widely recognized. For these reasons, in the IPF setting, thermal ablation procedure, generally performed under CT guidance, can be a viable therapeutic option. Radiofrequency ablation and SBRT in patients with inoperable stage I NSCLC had similar overall survival rates while local progression rates were higher for radiofrequency ablation.[246] No specific comparison had been performed over different types of ablative procedures (radiofrequency, microwave, cryoablation) while the largest experience came from radiofrequency ablations. Every technique has its own advantages and disadvantages (e.g., cryoablation is safer near the airways while microwaves are powerful and faster than radiofrequency) that can be a further strength of minimally invasive procedure. At the same time this heterogeneity creates severe difficulties in obtaining large databases of procedures outcome and procedures performances. For these reasons a multidisciplinary advice and centre preferences and expertise are fundamental for alternative treatment choice and management.

Advanced Cell Therapies

Based on the U.S. Food and Drug Administration (FDA) cell therapy includes cellular products for immunotherapies, cancer vaccines, and other types of both autologous and allogeneic cells for certain therapeutic indications (www.fda.gov). According to this definition, the most clinical implications regard clearly cancer, but the recent progresses in the knowledge of molecular mechanisms responsible of IPF with the evidence of biologic similarities between IPF and malignant proliferation give a strong rationale for the investigation and development of cell therapeutic strategies and tissue engineering to impair fibrotic damages. MSCs feature the pluripotent capacity of and their ability to differentiate to important lineages that can modulate on immunity, impair inflammatory reactions, and promote epithelial tissue repair;[247] the clinical application of MSC therapy has been shown to be feasible and safe in humans with IPF (www.clinicaltrial.gov) and several data have been already published.[248–252] A schematic representation of the application of MSCs in lung fibrosis is reported in Figure 3. MSCs and fibrocytes can be generated from the bone marrow and home to the injured lungs in response to several secreted chemokines and growth factor receptors.[253,254] Lung resident MSCs (LR-MSCs) and mainly myofibroblasts precursors have been detected as well.[255,256] Allogenic MSCs derived from unrelated donors seems to be safe as homologous obtained cells when infused in patients carrying mild-moderate disease.[257] MSCs communicate with their surrounding microenvironment and in particular, the alveolar niche cells promote alveolar epithelial progenitors to regenerate the damaged epithelium.[258] Different strategies have been explored to the development of advanced cellular therapy in IPF. The MSCs quiescence or dormancy is a key feature of stem cells; thus, a potential target of therapeutic intervention is that of inducing stem cells into the cell cycle to start differentiation. In this perspective, the Wnt/β-catenin signalling is known to be implicated IPF pathogenesis since its activation inhibits MSCs to differentiate into epithelium. The pharmacological inhibition of the Wnt cascade might be exploited to impair myofibroblasts differentiation and proliferation.[259,260] Moreover, MSCs in IPF become rapidly senescent[261–263] and strategies to ameliorate this process are beneficial in reducing disease progression. miRNAs are involved in mediating MSC senescence by modulating the expression of several pathways. Very recently, miR-200 family members (miR-200b-3p and miR-200c-3p) and miR-199a-5p has been reported to regulate MSC senescence in IPF patients with by acting on the Sirtuin 1/AMP-activated protein kinase signalling cascade; thus, they emerge as a novel potential target to rejuvenate IPF-MSCs and to prevent fibrotic damages and to restore proper differentiation.[264,265] MSCs display immunomodulatory properties and can secrete anti-fibrotic factors (Figure 4). It has been reported that lung resident MSC can be in IPF lungs and their secretome is able to damage fibroblast proliferation while promoting enhanced epithelial wound repair via several growth factors, among which hepatocyte growth factor (HGF).[266,267] Interestingly, inhaled lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) have been shown to attenuate bleomycin and silica-induced fibrosis in experimental models in a more effective manner that those derived from resident MSCs. They seem block EMT acting on WNT/beta catenin, Rho/Rock and TGFbeta 1/SMAD pathways.[268] Other therapeutic targets in the context of cell therapy in IPF are represented by MSC-derived growth factors, as HGF, which play relevant roles in the repair of alveolar epithelial cells, actively contrasts myofibroblasts activation and the abnormal deposition of ECM.[269] Growing evidence indicates that the changes in ECM composition and mechanical properties which characterize IPF can be exploited for therapeutic purposes. Synthetic materials as polyacrylamide, hydrogels, highly cross-linked polymer networks as well as liposomes, polymeric nanoparticles represent engineered platforms which can be decorated with cell-adhesive ligands, signalling factors, drugs which can modulate lung remodelling.[270–272]

Figure 3.

Stem cells and their application in lung fibrosis. Stem cells can be classified into embryonal stem cells (ESC), adult stem cells (ASC) and induced pluripotent stem cells (IPSC) according to their origin. ESCs derive from embryo blastocysts, ASC can be isolated from various tissues, such as bone marrow, lung, adipose tissue, umbilical cord blood, umbilical cord tissue and amniotic fluid. IPSC are obtained from somatic cells using reprogramming factors (OCT3/4, SOX2, C-MYC, KLF4), responsible for re-programming to pluripotency. Stem cells can be administrated intravenously, intratracheally or intraperitoneally. They migrate to the injured sites of the lungs where they differentiate in alveolar type II cells and exert anti-inflammatory, antifibrotic and immunomodulant actions. IPF, idiopathic pulmonary fibrosis.

Figure 4.

Stem cells and secretoma. Lung spheroid cells are round aggregates composed by stem cells and stromal cells. They produce a complex of proteins and growth factors, complexify named as secretoma, also including exosomes. Lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) reproduce a regenerative microenvironment and promote differentiation of stem cells towards epithelial phenotypes. EMT, epithelial mesenchymal transition.

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