Most of the human cancers are made by a variety of different cell type that together form the tumor mass. Cancer is in constant evolution, changing its behavior relative to where and when it grows in the human body, making the cure for this disease very challenging.
Researchers at the European Institute of Oncology (IEO) have reviewed all the recent molecular classifications for pancreatic adenocarcinoma, highlighting the complex heterogeneity of this tumor that probably account for the high rate of treatment failures.
Dr. Gioacchino Natoli and Dr. Giuseppe Diaferia (co-founder of I-PCC) at IEO, together with Dr. Marta Milan, now at the The Francis Crick Institute in London, explained how such heterogeneity can, to a large extent, be traced back to two main classes of PDAC cells that commonly coexist in the same tumor.
These cells having different sensitivity to drugs likely represent a major hurdle to overcome for effective chemotherapy or even targeted therapies. Even broad-spectrum chemotherapy, such as FOLFIRINOX, based on combination of different drugs (fluorouracil, irinotecan, oxaliplatin, and leucovorin) although significantly improves survival of PDAC patients compared with standard monotherapy with gemcitabine, is unable to efficiently eradicate all tumor cells resulting in high rate of relapse.
Ideally, a rationally designed combination of drugs or targeted therapies based on the properties and/or genetic makeup of at least the two main different tumor cell types composing most PDACs may optimize the balance between efficacy and and toxicity.
From Milan M, Diaferia GR, Natoli G. “Tumor cell heterogeneity and its transcriptional bases in pancreatic cancer: a tale of two cell types and their many variants”. EMBOJ 2021
In a study just published in the prestigious international journal Proceedings of the National Academy of Sciences of the USA, researchers from the Research Center in Experimental Medicine (CeRMS) and the Department of Molecular Biotechnology and Health Sciences of the University of Turin have discovered the way to allow the antitumor killer lymphocytes to infiltrate inside the tumor tissue to eliminate it.
Pancreatic cancer is referred to as a “silent killer”. The reason for this name derives from the fact that it does not present specific symptoms when it manifests itself, or rather, when these appear often they are associated with a very advanced stage of the disease. The cause could derive from the fact that, since its origin, pancreatic cancer is characterized by an intricate set of cells of different nature that surround the tumor and form the so-called “tumor microenvironment”. Numerous genetic and metabolic programs are activated in the microenvironment which have an enormous advantage in tumor growth and prevent the anti-tumor killer T lymphocytes from “infiltrating” the tumor tissue, confining them to the outside and preventing them from recognizing and eliminating the tumor.
Coordinated by Prof. Paola Cappello and Prof. Francesco Novelli, the researchers have shown that by blocking interleukin 17A, an important messenger of communication between the cells of the immune system and between these and the surrounding cells, the tumor “microenvironment” changes, affecting in particular the behavior of a type of cell, the fibroblasts. These cells are particularly abundant in pancreatic cancer and are responsible for the deposition of a complex and compact network of fibers, the so-called “matrix”, which represents the greatest obstacle to the entry of antitumor killer lymphocytes as well as the spread of drugs used for the treatment.
Dr. Gianluca Mucciolo, first author of this study, used an animal model predestined to develop pancreatic cancer and lacking the ability to produce interleukin 17°. He observed that, despite the presence of many fibroblasts, the tumor microenvironment was more ” Invaded ”by antitumor killer lymphocytes. Thanks to a collaboration with a research group of the Czech Academy of Sciences in Prague, led by Professor Luca Vannucci, the Turin group demonstrated that in the absence of interleukin 17A, the matrix deposited by the fibroblasts was, unlike usual, much softer and lax, and presented an architecture that had little in common with the real “highways” that favor the invasion of tumor cells of the surrounding tissues.
To thoroughly analyze the behavior of fibroblasts in pancreatic cancer, Professor Cappello returned to the Campbell Family Institute for Breast Cancer Research in Toronto in Professor Tak Mak’s direct laboratory, and by using of sophisticated technologies for the study of gene expression at the level of a single cell, she has shown that in the absence of interleukin 17A, pancreatic tumor fibroblasts modify their gene program to promote both the accumulation of anti-tumor T lymphocytes and increase in their killer activity.
“Although further studies are needed to investigate the role of this interleukin in the anti-tumor response in pancreatic cancer, the great news is that anti-interleukin 17A antibodies are already being used in clinical practice to limit the damage of autoimmune diseases and therefore they could be combined with other strategies to target pancreatic cancer from more than one place and make the different treatments more efficient ”, Prof.ssa Cappello said.
These data add a new building block to promote an effective strategy for treating pancreatic cancer. Prof. Novelli said: “Our group has recently developed a therapy based on DNA vaccination and chemotherapy which in the animal model has shown remarkable efficacy in blocking the progression of the tumor. This efficacy could be increased by the combined administration of anti-interleukin 17A antibodies, triggering the antitumor activity of killer lymphocytes ”.
From the study of the tumor microenvironment and the mechanisms by which the immune system can react against pancreatic cancer, new combined therapies are born that allow us to “encircle” this tumor more and more and to open concrete prospects for its defeat.
“IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions, Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2020395118. doi: 10.1073/pnas.2020395118”