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Targeting immunosuppression for cancer therapy
Cristina Ghirelli and Thorsten Hagemann
Barts Cancer Institute, John Vane Science Centre, London, United Kingdom.
Address correspondence to: Thorsten Hagemann, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, 3rd Floor, London, EC1M 6BQ, United Kingdom. Phone: 442078825795; Fax: 442078826110; E-mail: t.hagemann@qmul.ac.uk.
Find articles by Ghirelli, C. in: JCI | PubMed | Google Scholar
Barts Cancer Institute, John Vane Science Centre, London, United Kingdom.
Address correspondence to: Thorsten Hagemann, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, 3rd Floor, London, EC1M 6BQ, United Kingdom. Phone: 442078825795; Fax: 442078826110; E-mail: t.hagemann@qmul.ac.uk.
Find articles by Hagemann, T. in: JCI | PubMed | Google Scholar
Published May 24, 2013 - More info
J Clin Invest. 2013;123(6):2355–2357. https://doi.org/10.1172/JCI69999.
© 2013 The American Society for Clinical Investigation
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Abstract
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
Authors
Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy
Immunotherapies have potential for the treatment of cancer, because immune-based therapies act through a mechanism that is distinct from chemotherapy or radiation therapy and because they represent non-cross-resistant treatments, with an entirely different spectrum of toxicities. Both T and B cells are capable of recognizing a diverse array of potential tumor antigens through the genetic recombination of their respective receptors, and, more importantly, both T and B cells can distinguish small antigenic differences between normal and transformed cells, providing specificity while minimizing toxicity (1).
Several studies have sought to characterize aspects of the immunosuppressive tumor immune microenvironment and the mechanisms that may be responsible (2). There is clinical and preclinical evidence that activation of an antitumor immune response can result in tumor regression and provide clinical benefit, but the natural CTL immunity against tumors often falls short of preventing the development of malignancies. Attempts to maximize the natural response include using antibodies (e.g., anti–CTLA-4–blocking antibodies ipilimumab and ticilimumab) and vaccines (e.g., Provenge) as well as cytokines (e.g., IL-2) (3). However, the clinical response rates to these interventions remain low, and there are currently no clear means to identify either patients who may respond to therapy or identify markers of response in patients that have demonstrated some clinical benefit. Immunotherapy aimed at harnessing endogenous antitumor immunity by modifying immune regulatory mechanisms has shown promise in multiple tumor types (3, 4). However, in order to unleash the full potential and exquisite specificity of the antitumor immune response and achieve the best clinical responses, the multiple immunosuppressive networks co-opted by tumors need to be defined and collectively overcome (4).
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Unanswered questions
The effectiveness of the antibody-mediated immune response is, as outlined above, influenced by several components systemically and within the tumor microenvironment. To what extent does the addition of antiinflammatory drugs influence and potentially enhance the immune response? FcγR is expressed on a variety of effector cells, such as macrophages, neutrophils, mast cells, and NK cells, and complement factors are present in the tumor microenvironment, so the interaction of the Fc part of the therapeutic antibody bound to its tumor antigen will initiate an inflammatory response of some kind. This response is crucial to orchestrate the right influx of leukocytes, resulting in lysis of the target cells (antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity). However, it is also clear that cancer-related inflammatory processes in the microenvironment of the tumor mediated by binding of endogenous antibodies can also orchestrate the protumor function of myelomonocytic cells (25). The possibility that these tumor-fostering mechanisms initiated by the therapeutic antibodies can also play a role in tumor treatment and potentially dampen the overall response cannot be excluded.
Perhaps the reason that Marabelle et al. (13) see such a strong systemic effect of their approach is that they guide the immune response away from the immunosuppressive microenvironment of the primary tumor and toward distant sites in which immunosuppression has not yet been established. Do the observations hold true in the absence of a strong antigen? What are the team players involved locally in generating this significant systemic effect? Marabelle et al. certainly observed an effect on lung metastasis from 4T1 tumors; however, will the proposed approach provide an effect on the primary tumor if the metastatic lesion(s) is treated instead? This would be far more feasible for patients in many clinical settings.
As our understanding of the potential of immunotherapy expands, so does the list of research questions that will need to be answered before this approach can be translated for effective clinical use (Figure 1). How long would we need to treat patients with immune modulatory therapies? What is the best combination of approaches? And last, we need a clearly defined clinical read-out for therapeutic response. Our understanding of the evolution of immune escape is still incomplete, and additional work must be done to identify those patients who will benefit most from immunotherapy and to develop novel strategies.
Figure 1Marabelle et al. showed how local immunotherapy in mice helps the eradication of tumors at distant sites, even in an immune-privileged site such as the brain. This study opens several questions, and how these findings may translate to human immunotherapy is still a matter of debate.
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