Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes

Abstract

The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.

Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma

“…So far, targeted molecular and immunotherapeutic approaches, which have brought revolutionary therapy successes to the treatment of other solid malignancies, could not significantly improve the treatment of PDAC patients. To overcome the current therapeutic deficits, ongoing research aims to further decipher the opaque microenvironment of the pancreatic tumour, the high genetic instability of the cancer and, increasingly important, the immune microenvironment of PDAC [ 18 ].…”

Visceral Surgery Profoundly Affects the Cellular and Humoral Components of the Anti-Tumour Immune Response in a Murine Pancreatic Adenocarcinoma Model

“…The immune microenvironment of PDAC has been characterised as immunosuppressive and up to now, immunotherapeutic approaches to this tumour entity have mostly shown unsatisfactory results [ 23 , 29 ]. This is mainly due to several immune escape mechanism of the pancreas tumour (i.e., the release of immune-suppressive chemokines or cytokines by the tumour and the establishment of a barrier of fibroblasts and collagen [ 30 ]). There are numerous clinical studies under progress that have different strategies in immunological treatments against PDAC [ 31 ].…”

Nanoparticle-Based Therapeutic Strategies for Enhanced Pancreatic Ductal Adenocarcinoma Immunotherapy

“…Two key problems hinder the therapeutic effects of PDAC immunotherapy: the inadequate response caused by the immunosuppressive TIME and the delivery obstacle presented by the dense tumor stroma and hypovascularization [ 8 ]. Recent studies show that nanoparticles could help solve these problems.…”

“…Stromal cells can also induce immunosuppressive tumor cells [ 7 ]. Moreover, the infiltration of immunosuppressive cells, including regulatory T (Treg) cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), was reportedly rich, while immunosupportive cells, such as intratumoral CD8 + T cells, were relatively scarce in the PDAC tumor microenvironment [ 8 , 9 ]. Additionally, PDAC is a hypovascular tumor accompanied by hypoxia and a high interstitial fluid pressure (IFP) in the tumor microenvironment (TME), which impairs drug delivery and leads to immunosuppression [ 10 ].…”