Cancer Immunotherapy: Immune Suppression and Tumor Growth

Breaking tolerance: improving cancer immunotherapy
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There are several matrisome glycoproteins that mediate cellular interactions and define the structure of a tissue along with collagens. Laminins form the basement membrane that is a potentially important barrier to infiltration of immune cells in the matrix. Laminins, in particular laminin , regulate structural intregrity of basement membrane and promote epithelial-to-mesenchymal transition EMT resulting in tumor invasion and metastases [ , ]. Fibronectin and elastin comprise the interstitial matrix and are modulated by fibroblasts. Fibronectin is upregulated by angiogenic growth factors including VEGF.

Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers

Glycosaminoglycans, including hyaluronan HA , heparin, heparan sulfate, and chondroitin sulfate, are key macromolecules that affect cell migration and growth by acting directly on cell receptors or via interactions with growth factors [ ]. HA is an abundant component of the matrix that modulates immune cells, by interactions with TLRs and CD44, and influences tumor growth via regulation of cellular differentiation and angiogenesis [ ].

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HA give dense architecture to TME impeding the infiltration of drugs and effector immune cells [ ]. Functions of HA vary according to the size. Low molecular weight HA induces inflammation and angiogenesis, inhibits fibroblast differentiation and stimulates pattern-recognition receptors [ , , , ].

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

High molecular weight HA is anti-angiogenic, promotes structural integrity, and suppresses the immune system by increasing activity of Tregs [ , , ]. Proteoglycans contain repeating glycosaminoglycans that bind several cytokines and growth factors in the matrix. Heparan sulfate proteoglycans HSPGs , including transmembrane syndecan , glycosylphosphatidylinisotol GPI -anchored glypican , secretory granule-derived serglycin and secreted HSPGs perlecan, agrin and betaglycan , are large heterogeneous molecules that interact with growth factors, chemokines and structural proteins of the ECM to influence cellular differentiation and tumor progression [ , , ].

Enzymatic degradation of HSPGs has been demonstrated to promote tumor infiltration and antitumor activity of chimeric antigen receptor CAR -T cells [ ]. Small leucine-rich proteoglycans SLRPs , include decorin, biglycan, fibromodulin, podocan, keratocan, and others. Versican VCAN , a chondroitin sulfate proteoglycan, is normally present in small quantities in soft tissues but it accumulates in the inflamed cancerous and non-cancerous tissues [ ].

It interacts with cells and stromal matrix components to regulate cell proliferation, migration, and activation. VCAN accumulation induces inflammation, and recruits and activates immune-suppressive myeloid cells [ , , , , , ]. It exerts tolerogenic effects by binding to TLR-2 in the tumor-infiltrating myeloid cells to promote immune evasion and tumor progression [ 26 , , , , , ].

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High VCAN expression results in enhanced tumor invasion in gastric and cervical cancers [ , ]. Cleavage of matrisome proteins by matrix-remodeling enzymes generates a wide variety of bioactive peptide fragments, the matrikines, which may act as chemokines or cytokines. Matrix metalloproteinases MMPs and adamalysins, including A disintegrin and metalloproteinases ADAM and A disintegrin and metalloproteinase with thrombospondin motifs ADAMTS , are major families of the matrix enzymes that produce matrikines, many of which have unknown functions [ , ].

Matrikines have a critical role in the infiltration of immune cells in TME and interact with immune regulators like TLRs. Elastin-derived matrikines act as chemokines for fibroblasts and up-regulate collagenase in lung cancer cells [ ]. Laminin fragments influence EMT [ ]. VCAN proteolysis is associated with CTL infiltration in colorectal cancer, regardless of mismatch repair status, and versikine promotes T cell infiltration through regulation of Batf3-DCs [ ].

MMPs have been associated with tumor progression and angiogenesis [ ]. There have been several negative phase III clinical trials of MMP inhibitors, primarily because of non-specificity of drugs and complex context-specific roles of MMPs [ , ].

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ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in several tumor types with varying degree of proteomic expression [ ]. ADAMTS-mutated cases have higher chemotherapy response rates and better survival in ovarian cancer [ ]. Tissue inhibitors of metalloproteinases TIMPs antagonize matrix proteases and affect major signaling pathways by regulating proteolytic processing [ ]. Matrix proteases are also regulated by various transcriptional factors, cytokines and growth factors that orchestrate the cellular cross-talk and modulate immune and inflammatory responses [ ].

The cancer-immunity cycle, proposed by Chen and Mellman, provides a critical framework to evaluate anti-tumor immune response. It progresses through the immune-mediated tumor cell death and release of tumor antigens, tumor antigen uptake and presentation, priming and activation of T cells, trafficking of T cells, tumor infiltration of T cells and recognition of tumor cells [ ]. The sustained immune response depends on the accumulation of immune-stimulatory factors and depletion of inhibitory factors.

Matrix remodeling plays a vital role in cancer-immunity cycle by modulating immune regulatory feedback mechanisms. Stromal matrix components alter the immune milieu by several mechanisms and modulate differentiation, migration, infiltration and polarization of immune cells in the TME Fig. Multiple roles of the extracellular matrix ECM in modulating the cancer-immunity cycle.

The cancer-immunity cycle progresses through tumor cell death and release of tumor antigens, tumor antigen presentation, priming and activation of T cells, trafficking of T cells, T-cell infiltration of tumor and recognition of tumor cells by effectors. Matrix remodeling shapes the inflamed immune microenvironment and plays a vital role at each step of the cancer-immunity cycle. Versikine promotes differentiation of the potent immune-stimulator Batf3-cDCs. Endothelial cells, adhesion molecules and chemokines modulate trafficking of leukocytes.

Stromal cells, including endothelial cells, pericytes and CAFs, and extracellular matrix components including collagens, GPs, GAGs and PGs, regulate infiltration and polarization of immune cells. Matrikines, cytokines and laminins regulate priming and activation of T cells. Matrix proteases and matrikines, including versikine, exert direct effects on immune cell polarization and activation. ICIs block immune checkpoints to induce anti-tumor immunity; however, the tumor matrix regulates generation and proliferation of the sustained host immune response.

Matrix-derived immune biomarkers promise an innovative approach to predict response to novel immunotherapies. Matrix-remodeling enzymes and matrikines, including versikine, exert direct effects on immune cell polarization and activation. They interact with immune receptors like TLRs and act as cytokines and chemokines to shape the direction and amplitude of the immune response.

Versikine appears to have a role in promoting local differentiation of the potent immunostimulator Batf3-cDC subset through IRF8 modulation [ , ]. Endothelial cells, pericytes and adhesion molecules modulate trafficking and infiltration of leukocytes. Collagens and glycoproteins, like laminin and fibronectin, regulate transmigration and polarization of immune cells in both lymphoid tissue and TME. A systematic understanding of matrix remodeling and the inflamed TME generated by stromal elements will help to identify investigational targets for development of novel immune biomarkers and combination immunotherapy.

The detection of VCAN proteolysis in the TME may provide a convenient and reliable immune biomarker that can be utilized across tumor types. Several attractive attributes underscore a potential role for VCAN proteolysis detection in this regard. Firstly, the proteolytic events do not appear to be tumor-specific and may be truly tumor-agnostic [ , ].

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Art Johnson August 7, 0 Comments As the saying goes, the point on a pencil is the inspiration and the other end with the eraser is the experience. Contributing to Cancer Research. Matrix metalloproteinases MMPs and adamalysins, including A disintegrin and metalloproteinases ADAM and A disintegrin and metalloproteinase with thrombospondin motifs ADAMTS , are major families of the matrix enzymes that produce matrikines, many of which have unknown functions [ , ]. Signalling from adenosine receptors to mitogen-activated protein kinases. A 2B and A 3 adenosine receptors modulate vascular endothelial growth factor and interleukin-8 expression in human melanoma cells treated with etoposide and doxorubicin. In the end, we provided a novel approach to rationally design dual or triple inhibitory chemotypes that can concomitantly hit several tumor-promoting pathways and increase the immune effector response by blocking myeloid cell-mediated tumor immunosuppression. Art Johnson August 7, 0 Comments.

Secondly, simple immunohistochemistry on standard, paraffin-embedded tissue is used, thus broadening the range of accessible samples to standard diagnostic samples collected in a variety of health care facility settings. Even decalcified tissue e. The development of novel immunotherapies, including ICIs, was the twenty-first century breakthrough in oncology. Although there have been durable remissions with the use of ICIs, less than third of the patients derive a benefit from these therapies. An often overlooked facet of immune regulation is the tumor matrix: a diverse and highly dynamic contributor that plays a vital role in the generation and proliferation of the host immune response.

Exploring transcriptional imprint and proteomic expression of stromal matrix components may identify promising predictive and prognostic biomarkers. VCAN proteolysis is one emerging paradigm of matrix remodeling and immune modulation.

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There has been major growth in understanding immune suppression mechanisms and its relationship to cancer progression and therapy. This book highlights. Cancer Immunotherapy. 2nd Edition. Immune Suppression and Tumor Growth. 0 star rating Write a review. Editors: George Prendergast Elizabeth Jaffee.

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