Current challenges in targeting tumor desmoplasia to improve the efficacy of immunotherapy

Desmoplasia is crucial for the development, progression and treatment of immune-resistant malignancies. and treatment of immune-resistant malignancies. Targeting desmoplasia-related metabolic pathways appears to be an interesting approach to expand our stock of disposable anti-tumor agents.CXCL12/CXCR4 axis inhibition reduces fibrosis, alleviates immunosuppression and significantly enhances the efficacy of PD-1 immunotherapy. CD40L substitute therapy may increase the activity of T-cells, downregulate CD40+, prolong patients’ survival and prevent cancer progression. Although FAPα antagonists used in preclinical models did not lead to permanent cure, an alleviation of immune-resistance, modification of desmoplasia and a decrease in angiogenesis were observed. Targeting DDR2 may enhance the effect of anti-PD-1 treatment in multiple neoplasm cell lines and has the ability to overcome the adaptation to BRAF-targeted therapy in melanoma. Reprogramming desmoplasia could potentially cooperate not only with present treatment, but also other potential therapeutic targets. We present the most promising metabolic pathways related to desmoplasia and discuss the emerging strategies to improve the efficacy of immunotherapy.

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The SDF1-CXCR4 Axis Functions through p38-MAPK Signaling to Drive Breast Cancer Progression and Metastasis

10.21236/ada517434 ◽

2008 ◽

Cited By ~ 1

Author(s):

Lyndsay Vanhoy

Keyword(s):

Breast Cancer ◽

P38 Mapk ◽

Cancer Progression ◽

Mapk Signaling ◽

Breast Cancer Progression ◽

Cxcr4 Axis

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Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

British Journal of Cancer ◽

10.1038/s41416-019-0666-4 ◽

2019 ◽

Vol 122 (1) ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Adrian L. Harris

Keyword(s):

Metabolic Pathways ◽

Trial Design ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Critical Role ◽

Therapeutic Approaches ◽

Preclinical Models ◽

Wide Range ◽

Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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TREX1 is a checkpoint for innate immune sensing of DNA damage that fosters cancer immune resistance

Emerging Topics in Life Sciences ◽

10.1042/etls20170063 ◽

2017 ◽

Vol 1 (5) ◽

pp. 509-515

Author(s):

Sandra Demaria ◽

Claire Vanpouille-Box

Keyword(s):

Dna Damage ◽

Immune Responses ◽

Cancer Cells ◽

Genomic Instability ◽

Cancer Progression ◽

Type I ◽

Replicative Stress ◽

Immune Resistance ◽

Cytoplasmic Dna ◽

Autoimmune Pathology

Genomic instability is a hallmark of neoplastic transformation that leads to the accumulation of mutations, and generates a state of replicative stress in neoplastic cells associated with dysregulated DNA damage repair (DDR) responses. The importance of increasing mutations in driving cancer progression is well established, whereas relatively little attention has been devoted to the DNA displaced to the cytosol of cancer cells, a byproduct of genomic instability and of the ensuing DDR response. The presence of DNA in the cytosol promotes the activation of viral defense pathways in all cells, leading to activation of innate and adaptive immune responses. In fact, the improper accumulation of cytosolic DNA in normal cells is known to drive severe autoimmune pathology. Thus, cancer cells must evade cytoplasmic DNA detection pathways to avoid immune-mediated destruction. The main sensor for cytoplasmic DNA is the cyclic GMP–AMP synthase, cGAS. Upon activation by cytosolic DNA, cGAS catalyzes the formation of the second messenger cGAMP, which activates STING (stimulator of IFN genes), leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated antiviral and antitumor immunity, and its production by cancer cells can be subverted by several mechanisms. However, the key upstream regulator of cytosolic DNA-mediated immune stimulation is the DNA exonuclease 3′-repair exonuclease 1 (TREX1). Here, we will discuss evidence in support of a role of TREX1 as an immune checkpoint that, when up-regulated, hinders the development of antitumor immune responses.

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Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽

10.3390/cancers13040870 ◽

2021 ◽

Vol 13 (4) ◽

pp. 870

Author(s):

Tomasz M. Grzywa ◽

Magdalena Justyniarska ◽

Dominika Nowis ◽

Jakub Golab

Keyword(s):

T Cells ◽

Tumor Growth ◽

Progenitor Cells ◽

Cancer Progression ◽

Immune Evasion ◽

Transforming Growth Factor ◽

Early Stage ◽

Interleukin 10 ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

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Antitumor effect of Batf2 through IL-12 p40 up-regulation in tumor-associated macrophages

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708598114 ◽

2017 ◽

Vol 114 (35) ◽

pp. E7331-E7340 ◽

Cited By ~ 13

Author(s):

Hisashi Kanemaru ◽

Fumihiro Yamane ◽

Kiyoharu Fukushima ◽

Takanori Matsuki ◽

Takahiro Kawasaki ◽

...

Keyword(s):

T Cells ◽

Cancer Progression ◽

T Cell Activation ◽

Cell Activation ◽

Antitumor Effect ◽

Leucine Zipper ◽

Cancer Prognosis ◽

Tumor Associated Macrophages ◽

Basic Leucine Zipper

The development of effective treatments against cancers is urgently needed, and the accumulation of CD8+ T cells within tumors is especially important for cancer prognosis. Although their mechanisms are still largely unknown, growing evidence has indicated that innate immune cells have important effects on cancer progression through the production of various cytokines. Here, we found that basic leucine zipper transcription factor ATF-like 2 (Batf2) has an antitumor effect. An s.c. inoculated tumor model produced fewer IL-12 p40+ macrophages and activated CD8+ T cells within the tumors of Batf2−/− mice compared with WT mice. In vitro studies also revealed that the IL-12 p40 expression was significantly lower in Batf2−/− macrophages following their stimulation by toll-like receptor ligands, such as R848. Additionally, we found that BATF2 interacts with p50/p65 and promotes IL-12 p40 expression. In conclusion, Batf2 has an antitumor effect through the up-regulation of IL-12 p40 in tumor-associated macrophages, which eventually induces CD8+ T-cell activation and accumulation within the tumor.

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Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy

Pharmacology & Therapeutics ◽

10.1016/j.pharmthera.2017.05.012 ◽

2017 ◽

Vol 179 ◽

pp. 158-170 ◽

Cited By ~ 45

Author(s):

Richard L. Sleightholm ◽

Beth K. Neilsen ◽

Jing Li ◽

Maria M. Steele ◽

Rakesh K. Singh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Cxcr4 Axis

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3'-Deoxy-3'-18F-Fluorothymidine PET Predicts Response to V600EBRAF-Targeted Therapy in Preclinical Models of Colorectal Cancer

Journal of Nuclear Medicine ◽

10.2967/jnumed.112.108456 ◽

2013 ◽

Vol 54 (3) ◽

pp. 424-430 ◽

Cited By ~ 18

Author(s):

E. T. McKinley ◽

R. A. Smith ◽

P. Zhao ◽

A. Fu ◽

S. A. Saleh ◽

...

Keyword(s):

Colorectal Cancer ◽

Targeted Therapy ◽

Preclinical Models

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IL-2–Targeted Therapy Ameliorates the Severity of Graft-versus-Host Disease: Ex Vivo Selective Depletion of Host-Reactive T Cells and In Vivo Therapy

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2011.11.016 ◽

2012 ◽

Vol 18 (4) ◽

pp. 523-535 ◽

Cited By ~ 12

Author(s):

Shai Yarkoni ◽

Tatyana B. Prigozhina ◽

Shimon Slavin ◽

Nadir Askenasy

Keyword(s):

T Cells ◽

Targeted Therapy ◽

Graft Versus Host Disease ◽

Ex Vivo ◽

Host Disease ◽

Graft Versus Host ◽

Selective Depletion

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LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis

Science ◽

10.1126/science.aan3975 ◽

2018 ◽

Vol 361 (6400) ◽

pp. 406-411 ◽

Cited By ~ 10

Author(s):

M. C. Poffenberger ◽

A. Metcalfe-Roach ◽

E. Aguilar ◽

J. Chen ◽

B. E. Hsu ◽

...

Keyword(s):

T Cells ◽

Cancer Progression ◽

Immune Cell ◽

Inflammatory Factors ◽

Gastrointestinal Polyposis ◽

Cancer Predisposition Syndrome ◽

Stat3 Signaling ◽

Liver Kinase B1 ◽

Peutz Jeghers Syndrome ◽

Transcription 3

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/− mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/− animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

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