Delivering a Double Whammy: Targeting Stroma to Improve Immunotherapy Outcomes in Pancreatic Ductal Adenocarcinoma

See “Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy,” by Blair AB, Wang J, Davelaar J, et al, on page 1267. See “Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy,” by Blair AB, Wang J, Davelaar J, et al, on page 1267. Pancreatic ductal adenocarcinoma (PDAC) remains a formidable public health enemy with a 5-year patient survival rate of only 11%.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2019.CA Cancer J Clin. 2019; 69: 7-34Crossref PubMed Scopus (14652) Google Scholar In most patients, it is hard to detect the disease at an early stage due to the innocuous early signs and rapid onset of aggressive metastasis. Despite decades of progress in understanding the pathobiology and availability of new drug regimens, PDAC is projected to become the second-leading cause of cancer-related mortality by 2030.2Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74 (Published correction appears in Cancer Res 2014;74:4006): 2913-2921Crossref PubMed Scopus (4424) Google Scholar In fact, one of the biggest disappointments in the field has been the dismal impact of immunotherapeutic strategies, which have enjoyed reasonable success against other malignancies such as lung, breast cancers, and melanoma, among others, in the treatment of solid, immunologically “cold” tumors such as PDAC.3Henriksen A. Dyhl-Polk A. Chen I. et al.Checkpoint inhibitors in pancreatic cancer.Cancer Treat Rev. 2019; 78: 17-30Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar,4Balachandran V.P. Beatty G.L. Dougan S.K. Broadening the impact of immunotherapy to pancreatic cancer: challenges and opportunities.Gastroenterology. 2019; 156: 2056-2072Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Thus, there is an urgent need for identifying novel strategies to treat PDAC and to understand whether the current treatment paradigms and available drugs can be redirected more effectively in the treatment of PDAC. To this end, the publication by Blair et al5Blair A.B. Wang J. Davelaar J. et al.Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy.Gastroenterology. 2022; 163: 1267-1280Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar provides a glimmer of hope by investigating the feasibility of targeting the PDAC stroma intracellular and extracellular signaling to sensitize the PDAC tumors to anti–programmed cell death protein 1 (PD-1) therapy. The PDAC stroma is a dense, fibrous barrier that contributes to the development of a hypoxic tumor microenvironment (TME) that posits a formidable resistance to any standard chemotherapeutic strategies. Previous studies have identified the key role played by tumor stroma in promoting the immunologically cold phenotype of PDAC and helping tumor cells evade the immune system.6Garg B. Giri B. Modi S. et al.NFκB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via up-regulation of CXCL12.Gastroenterology. 2018; 155: 880-891Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar,7Vennin C. Murphy K.J. Morton J.P. et al.Reshaping the tumor stroma for treatment of pancreatic cancer.Gastroenterology. 2018; 154: 820-838Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar The strategy to target stroma in PDAC is not new, and barring a few promising preclinical Phase I, II, and III studies, the field is littered with many failed endeavors.7Vennin C. Murphy K.J. Morton J.P. et al.Reshaping the tumor stroma for treatment of pancreatic cancer.Gastroenterology. 2018; 154: 820-838Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Protected by this dense stroma, the PDAC TME is filled with a variety of components, such as pancreatic stellate cells, cancer-associated fibroblasts (CAFs), increased infiltration of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells, blood vessels, and nerve cells and innervations, along with the extracellular matrix components such as collagen, fibronectin, laminin, and hyaluronic acid produced by the CAFs.8Delitto D. Delitto A.E. DiVita B.B. et al.Human pancreatic cancer cells induce a MyD88-dependent stromal response to promote a tumor-tolerant immune microenvironment.Cancer Res. 2017; 77: 672-683Crossref PubMed Scopus (20) Google Scholar These wide arrays of stromal components have been used as targets to design pharmacologic interventions that would reduce tumor growth or halt the progression of the diseases itself. One of the most popular targets is hyaluronan, with studies showing that a high deposition of hyaluronan in PDAC is associated with a poor prognosis.9Jacobetz M.A. Chan D.S. Neesse A. et al.Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer.Gut. 2013; 62: 112-120Crossref PubMed Scopus (748) Google Scholar Polyethylene glycosylated recombinant human hyaluronidase (PEGPH20) is a human recombinant PH20 hyaluronidase, and although many preclinical studies targeting PEGHPH20 alone or in combination with other standard-of-care drugs and other therapeutic agents have shown promise, the clinical trials are yet to deliver on the promise of this approach.10Hingorani S.R. Zheng L. Bullock A.J. et al.HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma.J Clin Oncol. 2018; 36: 359-366Crossref PubMed Scopus (298) Google Scholar, 11Ramanathan R.K. McDonough S.L. Philip P.A. et al.Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313.J Clin Oncol. 2019; 37: 1062-1069Crossref PubMed Scopus (174) Google Scholar, 12Van Cutsem E. Tempero M.A. Sigal D. et al.Randomized Phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma.J Clin Oncol. 2020; 38: 3185-3194Crossref PubMed Scopus (171) Google Scholar In a similar vein, inhibition of the focal adhesion kinase pathway by using defactinib, a competitive inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 in PDAC treatment, is currently being evaluated in a clinical trial (NCT03727880).13Clinical Trials.gov. NCT03727880: Study of Pembrolizumab With or Without Defactinib Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma.https://clinicaltrials.gov/ct2/show/NCT03727880Date accessed: July 22, 2022Google Scholar,14Neoptolemos J.P. Kleeff J. Michl P. et al.Therapeutic developments in pancreatic cancer: current and future perspectives.Nat Rev Gastroenterol Hepatol. 2018; 15: 333-348Crossref PubMed Scopus (576) Google Scholar Building on these results, Blair et al5Blair A.B. Wang J. Davelaar J. et al.Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy.Gastroenterology. 2022; 163: 1267-1280Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar hypothesize that because the stroma in PDAC serves as a physical barrier and shields the tumor from the immune system, combining a dual-stromal targeting strategy (using PEGPH20 and FAK inhibitor) would make the tumor more receptive to the actions of the anti–PD-1 antibody, thereby reducing tumor growth and even metastasis. Thus, the study evaluates the efficacy of a triple-therapy approach, combining PEGPH20 (or anti–C-X-C chemokine receptor type 4 [CXCR4] antibody, because PEGPH20 is currently not in clinical development) and FAK inhibitor (FAKi VS-4718, in mouse studies) along with anti–PD-1 antibody as a PDAC treatment strategy. The preclinical results clearly indicate the success of this approach. The authors began by evaluating whether PEGPH20 synergizes with FAKi to improve the response to anti–PD-1 antibody in a murine model of PDAC. Results show that this synergistic therapy approach increased survival and reduced tumor growth and metastasis by enhancing the effector T-cell infiltration (cluster of differentiation [CD]3+ CD8+) as well as the cytokine response for effector T-cell function and activation. Previous studies have already shown that in PDAC, low infiltration of tumors by T cells has been correlated with poor outcomes and that the presence of activated pancreatic stellate cells and CAFs have been reported to reduce T-cell infiltration of the tumor site, thus resulting in the immunologically cold phenotype that is typical of PDAC.5Blair A.B. Wang J. Davelaar J. et al.Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy.Gastroenterology. 2022; 163: 1267-1280Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,8Delitto D. Delitto A.E. DiVita B.B. et al.Human pancreatic cancer cells induce a MyD88-dependent stromal response to promote a tumor-tolerant immune microenvironment.Cancer Res. 2017; 77: 672-683Crossref PubMed Scopus (20) Google Scholar Thus, these findings provide hope that using this dual stromal-targeting strategy in conjunction with the anti–PD-1 antibody will have immune and stromal modulating effects that could potentially sensitize the PDAC tumor to immune checkpoint therapy interventions. The authors follow-up with additional impressive results, wherein FAKi is shown to regulate T-cell metabolism by altering the expression of T-cell modulating cytokines, mainly chemokine (C-X-C motif) ligand (CXCL) 12, a ligand of C-C chemokine receptor 2 (CCR2) that is mainly expressed on bone marrow–derived monocytes and activated effector T cells, and increases the effector T-cell levels within the tumor. Additionally, the combination of hyaluronic acid degradation coupled with anti–PD-1 antibody and FAKi treatments reduces the numbers of granulocytic-myeloid-derived suppressor cells and myeloid cells (CXCR4-expressing cells). Based on their results, the authors speculate that this synergistic triple-therapy combination targets the stroma/CAFs through 2 pathways, possibly one through the CXCL12/CXCR4/CCR7 axis and the other through the CCL12/CCR2 axis, the results being a marked reduction in tumor growth and metastasis in the murine PDAC and metastasis models. Delivering a multipronged attack on the stromal targets in this fashion is particularly effective in overcoming the multiple compensatory resistance mechanisms that contribute to the development of a pervasive immunosuppressive phenotype of PDAC. To conclude, the study by Blair et al5Blair A.B. Wang J. Davelaar J. et al.Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy.Gastroenterology. 2022; 163: 1267-1280Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar is one of the first of its kind in a preclinical setting to show the feasibility of targeting both the intracellular and extracellular components of the PDAC stroma, thereby providing powerful evidence for a combination therapy that involves the use of anti-CXCR4 antibody in combination with FAKi to enhance the sensitivity of PDAC tumors to anti–PD-1 therapy. Given the limited abilities of the currently available chemotherapeutic regimens in combating PDAC, we need a fresh approach toward identifying newer therapies and targets to make a difference. Thus, this study paves the way for identifying other potent anti-CXCR4, FAKi, and anti–PD-1 targeting therapeutic reagents or strategies that could be tested for efficacy in clinical trials, which could be immensely useful in finally ushering in the promise of immunotherapy in treating recalcitrant solid tumors. Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 TherapyGastroenterologyVol. 163Issue 5PreviewSimultaneous targeting of both intracellular and extracellular components of the stroma in pancreatic cancer can alter the tumor microenvironment, thereby improving immunotherapy response. Full-Text PDF