Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Abstract

Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA high ) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2 3þ primary breast tumors and approximately 40% of EGFR þ head and neck squamous cell carcinomas are HA high , and hypothesized that HA high tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA high tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA high tumor cells, and greatly enhanced trastuzumab-or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA high tumors, resulting in enhanced trastuzumab-and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA high matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA high tumors.

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

“…31,32 In vitro and in vivo studies have shown that depletion of HA as a result of treatment with PEGPH20 leads to increased natural killer (NK) cell access to HAHigh tumor cells and enhanced trastuzumab or cetuximab-antibodydependent cell-mediated cytotoxicity. 17 This further supports the belief that surrounding PDA tumors, the HA matrix forms a barrier that inhibits monoclonal antibody and NK cell access; this barrier can be overcome using PEGPH20. In tumor cell membranes, CD44 receptors and receptors for hyaluronan mediated motility (RHAMM) bind and anchor the HA matrix, and this association is believed to enhance receptor tyrosine kinase activity that drives tumor progression and increases treatment resistance.…”

“…13,14 Accumulation of HA in tumors may also act as a barrier to immune cells, including T lymphocytes and macrophages, creating an immune suppressed microenvironment. [15][16][17] Increased HA also prevents chemotherapeutic agents and monoclonal antibodies from reaching their sites of action. 8,9 HA accumulation in the TME is associated with accelerated tumor growth and is an independent, negative predictor of survival.…”

“…8 Preclinical studies have also shown that PEGPH20-mediated HA reduction facilitates immune cell access to the TME, and increases CD8+ T cell recruitment to tumor sites. 17,28 In animal models of PDA treated with PEGPH20 plus chemotherapy or monoclonal antibodies, the biophysical effects of HA degradation by PEGPH20 translate into reduced tumor growth and improved survival. 9,10,12,29,30 In addition, adenosine, antibodies, and other molecular receptors are involved with dampening inflammation caused by HA degradation.…”

Tissue mechanics regulate brain development, homeostasis and disease

“…Cells which have undergone EMT often present with an altered glycocalyx, the saccharide-protein network on the cell surface (Roy et al, 2011;Porsch et al, 2013;Moustakas and Heldin, 2014). A strong glycocalyx elicits pro-tumorigenic effects by enhancing focal adhesion formation and downstream signaling (Paszek et al, 2014), and has also been implicated in resistance to small-molecule and antibody therapies because it provides a physical shield to the cell membrane and its associated receptors (Yang et al, 2013;Thompson et al, 2010;Singha et al, 2015). Indeed, in GBMs, we find that glycocalyx bulk augments mechanical signaling (unpublished data).…”

Pancreatic cancer: treatment approaches and trends

“…Regardless of the advances in pancreatic tumor biology knowledgment, mechanisms associated with the tumor microenvironment remain poorly understood, highlighting that the distinct composition of pancreatic tumor microenvironment could be a great barrier for immunotherapy success [92] . As a consequence of newly emerging information about tumor microenvironment, there was a shift in the cancer development concept from a tumor cell-centered view to a complex tumor ecosystem, which led to the acceptance that cancer cells interact with the extracellular matrix (ECM) and stromal cells [93,94] .…”