Review
Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses

https://doi.org/10.1016/j.it.2020.03.003Get rights and content

Highlights

  • Immune checkpoint blockade is not effective in immune-excluded and -desert tumors due to an immunosuppressive tumor microenvironment and the absence of activated T cells.

  • TGF-β is a pleiotropic cytokine that contributes to immune exclusion and evasion in various cancer types.

  • The therapeutic efficacy of oncolytic viruses is built on the recruitment of T cells and the induction of tumor-reactive immunity.

  • Oncolytic virotherapy and inhibition of TGF-β signaling, either alone or in combination, are two emerging approaches to increase the susceptibility of immune-silent tumors to immune checkpoint therapy.

In cancer immunotherapy, a patient’s own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-β (TGF-β)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-β signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade.

Section snippets

The Immune Profile of Solid Tumors Can Determine the Efficacy of Immunotherapy

Our immune system is able to respond to invading pathogens and initiate a protective immune response. Although malignant cells are more similar to the host than pathogens are, they still differ genetically, metabolically, and morphologically from normal cells and, therefore, can be recognized by the adaptive immune system, a trait called immunogenicity (see Glossary). In Box 1, we provide more information about processes involved in antitumor immunity. Immunotherapy is being extensively studied

Immune Checkpoint Inhibition Can Reinvigorate Dysfunctional Antitumor Responses in Immune-infiltrated Tumors

The discovery of immune checkpoints boosted the development of immunotherapeutic strategies against certain cancers. Programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are well-recognized immune checkpoint receptors that can limit antitumor immunity using distinct mechanisms. CTLA-4 prevents T cell activation by competing with the co-stimulatory molecule CD28 for binding to their common ligands CD80 and CD86 [5]. By contrast, PD-1 induces T cell

TGF-β as a Mediator of Immunosuppression

The secreted cytokine TGF-β is one of the key factors believed to be responsible for immune exclusion and suppression in certain types of cancer, such as pancreatic cancer, nonsmall cell lung cancer, and colon cancer [27., 28., 29.]. In premalignant lesions, TGF-β signaling suppresses tumor growth by inducing apoptosis and inhibiting cell proliferation [30]. However, during tumor progression, tumor cells become insensitive to TGF-β-induced cytostatic effects, and TGF-β functionally switches

Recruiting Tumor-specific Effector T cells Is the First Priority in Immune-desert Tumors

While immune-excluded tumors may benefit from combined checkpoint blockade and TGF-β inhibition, tumors with an immune-desert phenotype are less likely to benefit from this combination therapy [4,54]. Immune-desert tumors are characterized by an absence of T lymphocytes in both the tumor and surrounding stromal regions [4]. The absence of pre-existing antitumor immunity is the first barrier that needs to be overcome before checkpoint inhibitors and TGF-β blockade can be used.

Combining OVs with TGF-β Inhibition to Sensitize Solid Tumors for Immunotherapy

The lack of immunogenicity and the presence of stromal and immunosuppressive barriers are two major hurdles to effective immunotherapy for immune-desert tumors. Therefore, combined modulation of the stromal barrier by TGF-β inhibition and increasing immunogenicity using OVs might be a potent strategy to sensitize immune-desert tumors for T cell-based immunotherapy. Indeed, systemic treatment with a small-molecule TGF-βRI inhibitor in combination with a single intratumoral injection of oncolytic

Concluding Remarks

In this review, we discussed two promising therapeutic strategies to overcome barriers to effective immunotherapy in relation to the tumor immune phenotype. For the classification of tumor immune profiles, we relied on the three main tumor immune phenotypes postulated by Chen and Mellman [3]. We recognize that other classification strategies are possible, and more detailed profiles based on immunophenotyping of tumors are being investigated [21,79]. Immune-infiltrated tumors have an ongoing T

Acknowledgements

We sincerely apologize to authors for not citing their excellent work due to space limitations. This work was financially supported by a PhD fellowship from Leiden University Medical Center (to C.G.), the Dutch Cancer Society Bas Mulder Award 11056 (to N.v.M.), the Cancer Genomics Centre Netherlands (CGC.nl) and the Support Casper campaign by the Dutch foundation ‘Overleven met Alvleesklierkanker’ (supportcasper.nl). All figures were created with BioRender software (BioRender.com).

Glossary

Bispecific T cell engagers (BiTEs)
fusion proteins comprising two different single-chain variable fragments of monoclonal antibodies for simultaneous tumor cell binding and T cell activation.
Cancer-associated fibroblasts (CAFs)
cell type within the tumor stroma that can promote tumor progression by ECM remodeling and secretion of cytokines.
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)
immune checkpoint receptor that downregulates T cell responses.
Cytotoxic T lymphocytes (CTL)
CD8+ effector T

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