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    Topic review

    Cancer-Associated Fibroblasts and T Cells

    Subjects: Oncology
    View times: 9
    Submitted by: Helen Kaipe

    Definition

    CAFs release a number of different factors, including chemokines, cytokines, and growth factors, that promote immunosuppression through recruitment of immunosuppressive cells such as T regulatory cells (Tregs) and myeloid cells, upregulation of immune checkpoint molecules on T cells, and regulation of T-cell migration.

    1. Introduction

    Pancreatic cancer is projected to be the second leading cause of cancer-related deaths in 2030 as a result of the lack of an effective treatment and the increasing incidence rate [1]. The only potential cure for pancreatic cancer is surgery, but due to its late detection only 15–20% of the diagnosed patients present with resectable tumors, and with surgery alone, less than 10% survive 5 years or more. Resection followed by chemotherapy increases the 5-year overall survival to only 16–20% [2][3]. The standard treatment for unresectable tumors is chemotherapy but the median overall survival is at best 16 months [4].

    Although cancer immunotherapy has been shown to be effective against a variety of cancers during the last decade, there is very little progress in pancreatic cancer [5]. The majority of pancreatic tumors are defined as pancreatic ductal adenocarcinoma (PDAC), which is characterized by a dense stroma surrounding the cancer cells [6]. Release of extracellular matrix components by CAFs triggers fibrosis which obstructs the intra-tumoral vessels and prevents therapy delivery and infiltration of tumor-reactive immune cells. Therefore, it is likely that immunotherapy combined with other treatments targeting the stromal barrier could be promising for pancreatic cancer patients.

    CAFs release a number of different factors, including chemokines, cytokines, and growth factors, that promote immunosuppression through recruitment of immunosuppressive cells such as T regulatory cells (Tregs) and myeloid cells, upregulation of immune checkpoint molecules on T cells, and regulation of T-cell migration. It is still not well understood which factors are involved in regulating T-cell exhaustion and migration. However, several recent studies and subsequent clinical trials support that reprogramming of the suppressive microenvironment by blocking certain chemokine/chemokine receptor axes can improve immunotherapy outcomes in pancreatic cancer patients.

    2. Therapeutic Treatments to Target CAF-Derived Immunosuppressive Factors

    Several clinical trials have evaluated the benefit of targeting immunosuppressive factors in pancreatic cancer patients measured by clinical outcomes. However, to our knowledge, there are no studies investigating the effects on the immune profile after therapy. Table 1 includes a summary of the completed and active clinical trials targeting CAF-derived immunosuppressive factors in pancreatic cancer.

    Table 1. Immunosuppressive targets in the pancreatic tumor microenvironment used in preclinical models and clinical trials with the reported observations on the effects on immune cells and the primary end point of the clinical trial.
    Target Observations in Preclinical Models [ref] CLINICAL TRIALS
    NCT Treatment Phase Condition Status Primary Endpoint//
    Observations [ref]
    IL-6          
        NCT00841191 Siltuximab I/II Unresectable Completed CBR//
    No benefit
    =inflammatory cytokines
    =Angiogenesis markers
    ↓pSTAT3 [67]
    NCT02767557 Tocilizumab
    Gemcitabine
    Nab-paclitaxel
    II Unresectable Recruiting OS
    IL-6 + ICI
      ↓Tumor growth
    ↑Survival
    ↑T-cell infiltration [68]
    NCT04258150 Nivolumab
    Ipilimumab
    Tocilizumab
    SBRT
    II Unresectable Active ORR
    NCT04191421 Siltuximab
    Spartalizumab
    I/II Unresectable Recruiting Determine dose
    COX-2          
        NCT00176813 Celecoxib
    Gemcitabine
    Cisplatin
    II Unresectable Completed OS//
    No benefit [69]
      Celecoxib
    Gemcitabine
    II Unresectable Completed DFS/OS/tolerability//
    No benefit
    ↓VEGF [70]
      Celecoxib
    Gemcitabine
    II Unresectable Completed Toxicity/ORR//
    ↑OS
    ↓CA19.9 [71]
      Celecoxib
    Gemcitabine
    Irinotecan
    II Unresectable Completed Toxicity/ORR//
    ↑OS
    ↓CA19.9 [72]
    NCT03838029 Etodolac
    Propranolol
    Placebo
    II Resectable Recruiting DFS/biomarkers in blood
    NCT03498326 Celecoxib
    Gemcitabine
    II Resectable Recruiting DFS
    COX-2 + ICI            
      ↓Tumor growth
    ↑CD8+ T-cell infiltration [73]
    NCT03878524 Multiple drugs including Celecoxib
    Nivolumab
    II Unresectable Recruiting Find the best combination of drugs
    TGF-β          
        NCT00844064 AP 12009 I Unresectable Completed MTD//
    ↑OS
    NCT04624217 SHR-1701 I/II Unresectable Recruiting RP2D/ORR
    NCT03666832 TEW-7197 I/II Unresectable Recruiting DFS
    NCT03685591 PF-06952229
    Enzalutamide
    I Unresectable Recruiting DLT
    TGF-β + ICI            
      ↓Tumor growth
    ↑T-cell infiltration
    ↑CD8+ T-cell cytotoxicity [74,75]
    NCT02734160 Galunisertib
    Durvalumab
    I Unresectable Completed DLT//
    Limited effects [76]
    NCT04429542 BCA101
    Pembrolizumab
    I Unresectable Recruiting Safety/tolerability/DLT
    NCT02947165 NIS793
    PDR001
    I Unresectable Active DLT
    ref, reference; ICI, immune checkpoint inhibitor; NCT, clincialtrials.gov identifier; CBR, clinical benefit response; OS, overall survival; ORR, objective response rate; DSF, disease-free survival; MTD, maximum tolerated dose; RPD2, recommended phase 2 dose; DLT, dose-limiting toxicities; CA19.9, carbohydrate antigen; =, no changes; ↓, decrease; ↑, increase; //, separation between primary endpoint and observations.

    A phase I/II clinical trial (NCT00841191) assessing the safety and efficacy of anti-IL-6, siltuximab, administered as a monotherapy to patients with pancreatic cancer, showed a good tolerance, but did not detect any clinical benefit [7]. The efficacy of anti-IL-6 combined with immune checkpoint inhibitors or with chemotherapy is currently being studied in several clinical trials (NCT04258150, NCT04191421).

    The benefits of the COX-2 inhibitor, celecoxib, administered in combination with standard chemotherapy treatment, have been studied in several phase II clinical trials [8][9][10][11]. The treatment was well tolerated by the patients in all the studies but with varying clinical effects. Another study showed a 4-fold increase in one-year overall survival for patients treated with combination therapy compared to chemotherapy alone [11]. The benefits of COX-2 inhibitors are being further investigated in several clinical trials (NCT03838029, NCT03498326, NCT03878524).

    A phase I clinical trial (NCT02734160) evaluating anti-TGF-β-R1 combined with anti-PD-L1 in metastatic pancreatic cancer patients showed limited clinical effects with an objective response rate of only 3% and a median overall survival of 5 months [12]. The synergistic effect of anti-TGF-β and immune checkpoint inhibitors is being evaluated in different ongoing clinical trials (NCT04624217, NCT04429542, NCT02947165). Furthermore, a phase I/II clinical trial (NCT00844064) with advanced pancreatic cancer patients who received the TGF-β2 anti-sense oligonucleotide, OT-101, followed by subsequent chemotherapy, showed an improved overall survival [13]. Further clinical trials with anti-TGF-β are ongoing (NCT03666832, NCT03685591).

    3. Therapeutic Treatments to Target Chemokines

    T-cell infiltration into the tumor nest is crucial for a good prognosis in pancreatic cancer patients. As described above, many antagonists have been tested in preclinical animal models. However, only a few are currently being evaluated in clinical trials to treat pancreatic cancer patients. These include blocking of CCR2, CCR5, CXCR2, and CXCR4.Table 2 includes a summary of the completed and active clinical trials targeting chemokine receptors in pancreatic cancer.

    Table 2. Inhibitors of chemokines used in preclinical models and clinical trials with the reported observations on the effects on immune cells and the primary endpoint of the clinical trials.
    Target Observations in Preclinical Models [ref] CLINICAL TRIALS
    NCT Treatment Phase Condition Status Primary Endpoint//
    Observations [ref]
    CCR2          
      + CXCR2 target:
    ↓ MDSC infiltration [113]
    NCT01413022 PF-04136309
    Folfirinox
    Ib Unresectable Completed Optimal dose and toxicity//
    ↓TAMs
    ↑CD8+ and CD4+ T-cell infiltration [114]
    NCT02732938 PF-04136309
    Gemcitabine
    Nab-paclitaxel
    Ib/II Unresectable Completed DLT//
    No benefit
    Pulmonary toxicity [115]
    CCR5 + ICI          
        NCT04721301 Maraviroc
    Nivolumab
    Ipilimumab
    I Unresectable Active Safety and tolerability
    CCR2 + CCR5 + ICI            
        NCT03184870 Multiple drugs including BMS813160
    Nivolumab
    I/II Unresectable Active Toxicity/Tregs numbers/ORR/PFS
    CXCR1/2 + ICI          
      ↑ CD4+ and CD8+ T-cell infiltration [116,117]
    ↑ CD4+ and CD8+ T-cell cytotoxicity [116]
    ↓Neutrophils [116]
    ↓Metastasis
    ↓Tregs [117]
    NCT04477343 SX-682
    Nivolumab
    I Unresectable Recruiting MTD
    CXCL12/CXCR4 axis            
        NCT02179970 AMD3100 I Unresectable Completed Safety//
    ↑ T-cell, NK-cell infiltration and activation
    ↑ B-cell activation
    ↓CXCL8 [118]
    CXCL12/CXCR4 axis + ICI            
      ↑CD8+ T-cell infiltration and cytotoxicity [51] NCT03168139 NOX-A12
    Pembrolizumab
    I/II Unresectable Completed Safety//
    Stable disease
    ↑Th1 cytokines [119]
    NCT02826486 BL-0840
    Pembrolizumab
    IIa Unresectable Completed ORR//
    ↑OS
    ↑CD8+ T-cell infiltration
    ↓MDSC
    ↓Tregs [120]
    NCT04177810 AMD3100
    Cemiplimab
    II Unresectable Recruiting ORR
    NCT02907099 BL-0840
    Pembrolizumab
    II Unresectable Active ORR
    NCT04543071 BL-0840
    Cemiplimab
    Gemcitabine
    Nab-paclitaxel
    II Unresectable Recruiting ORR
    ref, reference; NCT, clinicaltrials.gov identifier; ↓, decrease; ↑, increase; MDSC, myeloid-derived suppressor cells; TAM, tumor-associated macrophages; ICI, immune checkpoint inhibitor; NK, natural killer cells; Th1, T helper type 1 cells; OS, overall survival; DLT, dose-limiting toxicities; ORR, objective response rate; PFS, progression-free survival; MTD, maximum tolerated dose; // separation between primary endpoint and observations.

    The safety and the efficacy of CCR2 blockade with PF-04136309, in combination with chemotherapy (folfirinox), has been shown in a phase Ib clinical trial in pancreatic cancer patients with advanced or borderline resectable tumors [14]. Blockade of the CCL2/CCR2 chemokine axis was well tolerated by the patients, which also showed a partial response. Combination treatment with chemotherapy resulted in a reduction in tumor-associated macrophages and an increased number of CD8+and CD4+T cells in the primary tumor compared to chemotherapy alone [14]. However, another safety and pharmacokinetics/pharmacodynamics phase Ib study which combined PF-04136309 and chemotherapy (gemcitabine/nab-paclitaxel) in patients with metastatic PDAC showed no significant improvement compared to chemotherapy alone but showed possible toxic effects in the lungs [15].

    Preclinical models in pancreatic cancer have shown that inhibition of the CCL5/CCR5 axis with maraviroc leads to tumor cell apoptosis and growth arrest [16]. Clinical trials in colorectal cancer with this drug (NCT01736813, NCT03274804) have shown promising results [17][18], with reduced proliferation of tumor cells and a shift towards M1 macrophages in one of the trials [17]. After these encouraging results, clinical trials with maraviroc combined with immune checkpoint inhibitors are currently ongoing for metastatic pancreatic cancer (NCT04721301). To boost the specific and encouraging effects of CCR2 and CCR5 antagonists, a phase Ib/II clinical trial with dual blockade of CCR2 and CCR5 with BMS 813160 as a monotherapy or in combination with chemotherapy or immunotherapy is currently ongoing for advanced pancreatic cancer patients (NCT03184870)

    Another chemokine antagonist that has been shown to alter the tumor immune environment is the CXCR1/2 antagonist SX-682. The main function of CXCR2 is to regulate the recruitment and migration of neutrophils and MDSCs. SX-682 has been shown to enhance Th1 immune response in several animal models including melanoma, breast, lung, and prostate cancer [19][20][21]. This inhibitor is currently undergoing a safety evaluation in a phase I clinical trial for pancreatic cancer patients in combination with anti-PD-1 treatment (NCT04477343).

    The CXCL12/CXCR4 axis excludes effector T cells from the tumor nests, impacting the efficacy of immune checkpoint inhibitors. The administration of the CXCR4 antagonist AMD3100 induced CD8+T cells infiltration and promoted a rapid activation and response of intratumoral T cells, natural killer cells, and B cells in a phase I clinical trial for metastatic PDAC [22]. The safety and clinical benefit of AMD3100 combined with anti-PD-1 treatment is being assessed in a phase II clinical trial (NCT04177810). A phase

    4. Conclusions

    Pancreatic CAFs have emerged as important regulators of the tumor microenvironment, both as restrainers of tumor growth but also as suppressors of tumor-reactive immunity. The recent discoveries about the diverse functions of different CAF subpopulations have significantly increased our understanding of the complex pancreatic stroma, but many questions still remain. The low mutational burden and the suppressive milieu in pancreatic cancer have been suggested to contribute to the lack of response to immune checkpoint inhibitors, but a key issue may be to assist T cells to efficiently come within close proximity of the malignant cells. Several lines of evidence suggest that chemokines and their cognate ligands play an important role in promoting T-cell exclusion from the tumor and further preclinical and clinical studies evaluating the role of chemokines are necessary to take full advantage of immune checkpoint therapeutics.

    The entry is from 10.3390/cancers13122995

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