Targeting Tumor Stroma: The Therapeutic White Space in Oncology

Tumor stroma, broadly defined as the non-cancer cell and non-immune cell components of tumors, is viewed traditionally as the structural components holding tumor tissues together. Identified more than 60 years ago, researchers are now beginning to fully appreciate the active biological role of stroma in transmission of signals in the tumor microenvironment, and the potential to modulate these signals for cancer therapy.

Tumor stroma and its role in cancer

Tumor stroma is composed of extracellular matrix and specialized connective tissue cells, including fibroblasts and mesenchymal stromal cells.¹ All tumors have stroma and require stroma for nutritional support and the removal of waste products, but stromal content can vary markedly in different types of cancers. For example, many lymphomas have minimal stroma whereas the stroma may make up 90% of other solid tumors.²

Cancer research has largely focused on biology intrinsic to cancer cells themselves - exploring processes within or on the surface of cancer cells including oncogenic signalling pathways. More recently, a role for the immune system in controlling tumor cells has been fully validated clinically, with concomitant increases in research efforts towards elucidating mechanisms of immune cell reactivity towards cancer cells. Stromal tissue is often overlooked, and rather seen as a biologically active ‘backdrop’ to both of these paradigms. In contrast, we consider stromal biology and stromal targeting approaches to be a conceptual and therapeutic white space in oncology.

Tumor stroma has been implicated in the resistance to multiple types of cancer therapy, consistent with an active biology in the tumor microenvironment. For example, the existence of certain cancer-associated fibroblasts (CAFs), a major type of stromal cell in tumors, can be predictive of cancer recurrence after chemotherapy treatment. Chemotherapy can directly induce DNA damage in CAFs, leading to changes in proteins secreted by these cells, which supports new tumor cell growth after initial treatment.¹ Therapy with certain targeted agents can affect CAFs in unexpected ways, inducing support of the cancer cells by fibroblasts and thus resistance to the therapy.³ Finally, when it comes to the impact of tumor stroma upon responses to immune-based cancer therapies, there is more to learn, but also clear examples of such interactions. For example, extracellular matrix factors are thought to affect the localization of T cells in some human tumors⁴, as well as being associated with resistance to checkpoint inhibitor therapies.⁵   

Adapted from: Valkenburg et al. Nat Rev Clin Oncol 2018 Jun;15(6):366-381. doi: 10.1038/s41571-018-0007-1.

The science of stromal modulation

At Boehringer Ingelheim we have placed tumor stromal biology research as a key pillar in our cancer immunology strategy (Four Pillars of Cancer Immunology Research | boehringer-ingelheim.com).

We hypothesize that a stromal-immune modulation approach can have meaningful impact for patients by releasing some of the suppressive mechanisms that enable tumors to become unresponsive to immunotherapy. Although removal/ablation of tumor stroma in cancer patients has yielded disappointing results,⁶ modulation of stromal-immune interactions may enable us to boost pathways that can support the immune system to combat tumors, potentially at the same time as reducing the effect of pathways that inhibit tumor immunity and/or support tumor growth. The goal of our research is to better understand tumor-stroma-immune interactions, which will hopefully lead to development of novel therapies that relieve immunosuppression in the tumor microenvironment and have the potential to benefit patients treated with multiple types of cancer therapies.

Leveraging complementary expertise in a multi-disciplinary approach

Scientific breakthroughs often occur at the interfaces of existing fields of research, with novel concepts and solutions being uncovered using multi-disciplinary perspectives and approaches. We are convinced that better understanding of the interface between tumor cell, immune cell AND stromal cell biology may provide scientific breakthroughs in cancer therapy. To that end, we have built a stromal biology team that includes expertise in all areas, providing complementary skills to unravel the impact of stromal interactions upon the tumor microenvironment.

A key challenge remains to develop models that allow us to study the relationships between tumor stromal phenotypes and immune landscape and reactivity. Many traditional in vivo cancer models arise from tumor cell lines that have been propagated for many years in culture and lack the ability to orchestrate the delicate interplay by which developing tumor cells influence surrounding stromal cells. We have addressed this challenge through collaborations with leading academic teams that have shared interests in these problems, and investment in genetically-engineered models of pancreatic and colorectal cancer. The pancreatic tumor models especially, contain relevant oncogenic driver pathways and display physiological amounts of tumor stroma, along with heterogeneity in immune cell infiltration, which allows dissection of tumor-stroma-immune interactions and testing of new therapeutic concepts in this area.

First-in-class stromal modulator

Periostin is a secreted signalling matricellular protein that is abundant in the immunosuppressive stroma of many solid tumors, including pancreatic cancers and certain types of colorectal cancers. Periostin binds to a variety of cells in the tumor microenvironment, including macrophages and myeloid cells as well as tumor cells, through integrin receptors.⁷ Studies have shown that periostin expression is associated with worse cancer outcomes and failure of PD-(L)1 blockade.^5,8-11

Development of our first-in-class stromal modulator, an anti-periostin antibody, provides an opportunity for Boehringer Ingelheim to lead the field in the testing of stromal-immune modulators in cancer therapy. It specifically inhibits the interaction of periostin with integrin receptors, which affects adhesion of tumor-associated macrophages. Pre-clinical results have shown that this novel compound decreases immune-suppressive macrophages and increases T cells in the tumor microenvironment. Thus, it has the potential to increase immune-permissivity in tumors and turn previously ‘cold’ tumors – non-reactive, immunologically inactive tumors – to ‘hot’ tumors that are susceptible to attack by the patient’s immune system.

Pioneering new approaches to transform patients’ lives

By understanding and modulating tumor stromal immune biology we are seeking innovative ways to boost responses to cancer cell-targeted therapies and immunotherapies, so patients can benefit from longer-lasting responses and improved outcomes. We know that patients are waiting for new and better treatments. Our team is working tirelessly to advance pioneering science around tumor stroma immune interactions so we can potentially develop new medicines that will change the face of cancer treatment and give new hope and more options to patients and their families.

Footnotes

1. Valkenburg KC, de Groot AE and Pienta KC. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 2018; 15: 366-381
2. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315(26):1650-9
3. Hirata E, et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signalling. Cancer Cell 2015; Apr 13;27(4):574-88
4. Salmon H, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Inv 2012;122(3):899-910
5. Chakravarthy A, Khan L, Bensler NP et al. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nature Communications 2018; 9, 4692 https://doi.org/10.1038/s41467-018-06654-8
6. https://www.halozyme.com/investors/news-releases/news-release-details/2019/Halozyme-Announces-HALO-301-Phase-3-Study-Fails-To-Meet-Primary-Endpoint/default.aspx
7. Gonzalez-Gonzalez L and Alonso J. Periostin: a matrixcellular protein with multiple functions in cancer development and progression. Frontiers in Oncology 2018 doi: 10.3389/fonc.2018.00225
8. Mariathasan S, Turley SJ, Powles T. TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 108; 554: 554-548
9. Hugo W, Zaretsky JM, Sun L et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016; 165: 35-44
10. Riaz N, Havel JJ, Makarov V et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017; 171; 934-949
11. Snyder A, Nathanson T, Funt SA et al. Contribution of systemic and somatic factors to clinical response and resistance of PD-L1 blockade in urothelial cancer: an exploratory multi-omic analysis. PLOS Medicine 2017 doi.org/10.1371/journal.pmed.1002309