How can we boost the immune response against tumours?

Cancer is a leading cause of death worldwide with an enormous socio-economic impact. We know that in principle a competent immune system should efficiently clear nascent tumors. However, tumors continuously avert endogenous immune checkpoints ultimately establishing their immune privilege. Today, cancer immunotherapy is an emerging option for cancer treatment. Indeed, one of the major challenges in the field is to depict precise mechanisms associated with tumor immune suppression.
My group takes up this challenge by unlocking an intriguing area of tumor immunology.

Background
Research
Group Members
Key Publications

Tumours are crowded lesions where cancer cells and host cells dynamically interplay by intricate cellular and molecular interactions. Among these, shaping immune cell subsets significantly influence cancer fate by their active recruitment within tumour microenvironment. This recruitment together with strategies adopted by tumour cells to sculpt host immune response drive the transition to a pro-tumorigenic condition, which in turns cause an impaired immune recognition of tumor cells. This transition is common also in chronic inflammatory status where immune cells contribute to generate molecular and cellular networks favouring carcinogenesis program.
Additionally, our group also investigates new pathways controlling cancer spreading. Indeed, metastases still cause of 90% of human deaths from cancer. A growing body of evidence suggested that the acquisition of invasiveness might require changes in biomechanical properties of tumor cells, which may be connected to the functional properties that are necessary for metastasis. We will meet these requirements by investigating novel molecular pathways controlling biomechanical properties of aggressive cancer cells. Our studies aim to unravel prevailing mechanisms orchestrating tumour immune evasion paving the way for innovative therapeutic opportunities. We are currently facing extensive questions in the field by means of multidisciplinary approaches ranging from proteomic analysis to intravital microscopy. Our research is nourished by fruitful on-going collaboration with other scientific teams in our institute.

The functional significance of post-translational modifications in tumour progression
Tumour microenvironment and its milieu influence immune response against cancer itself. In particular, the release and the overload of inflammatory reactive species are common features of the majority of cancer.
We recently defined a novel mechanism of tumour immune evasion established by the intratumoral generation of reactive nitrogen species (RNS). Post-translation modifications (PTMs) of proteins by reactive species represent an important additional level of functional regulation within the tumour environment, which requires further investigation. The network of possible RNS-induced protein modifications and the impact of such changes on the biology of the affected proteins are poorly explored but still and highly innovative field. Tumour setting might just represent the forefront of this investigation since RNS are produced in a number of inflammatory situations leading to pathological consequences such as in autoimmune and degenerative diseases. We are currently seeking other important RNS targets that can explain the immune modulation in the context of cancer and inflammation. We are investigating PTM upon RNS action, both for the molecular and functional aspects of cytokine modification. Starting from intriguing clues about the structure and the dynamics of key cytokines, we plan to investigate the consequences of these modifications in the carcinogenesis and in the shift of the immunological response towards immune tolerance.

Control of nuclear plasticity in metastatic cells
Metastasis represents a multi-step process involving tumor cell migration and finally growth at the new target organ. Despite significant advance in the field, metastases still cause 90% of human deaths from cancer. Therefore, understanding the mechanisms governing tumor cell invasion and metastasis represents an imperative step for reducing cancer mortality. To metastasize, a cancer cell must overcome multiple hindrances as the migration through the dense stromal matrix, intravasation and extravasation. All these events are directly associated with the physical properties of tumor cells. The acquisition of invasiveness appears to require changes in mechanical properties of cancer cells, which may be linked to the functional properties that are necessary for metastasis. De facto, highly metastatic cells generally show a softer cytoplasm compared to non-metastatic cells in many types of cancers. Over the last years, much of the research in the field has successfully upgraded measurements of the whole cell stiffness dealing with the mechanics of the cytoskeleton. Nonetheless, it is now clear that the mechanical properties and plasticity of the cell nucleus may play a major role in cancer metastasis, as the deformability of this largest and stiffest cellular organelle represents a prominent obstacle during the passage through interstitial space and narrow capillaries. The nuclear stiffness must be therefore tightly controlled and modulated during cell migration. Additionally, changes in nuclear stiffness and chromatin remodeling affect the transcriptional activity of metastatic cancer cells. On the basis of our preliminary data, we hypothesized that signals controlling cell migration might control nuclear stiffness. Understanding the alterations in the nuclear mechanics of metastatic cells will allow the identification of new targets, which can be pharmacologically exploited to control cancer spreading.

Andrielly H. Agnellini

PhD

Bianca Calì

PhD

Elisabetta Marcuzzi

PhD student

  1. Calì B, Molon B, Viola A. Tuning cancer fate: the unremitting role of host immunity. Open Biol. 2017 Apr;7(4). pii: 170006. doi: 10.1098/rsob.170006. PMID 28404796
  2. Marigo I., Zilio S. Desantis G., Mlecnik B., Agnellini A., Ugel S., Sasso M., Qualis J., Kratochvill F., Zanovello P., Molon B., Iezzi M., Lamolinara A., Ries C., Runza V., Hoves S., Biloco G., Bindea G., Mazza E., Bicciato S., Galon J., Murray PJ. And Bronte V. T cell cancer therapy requires CD40-CD40L activation of TNFalpha-iNOS producing dendritic cells. Volume 30, Issue 3, 12 September 2016, Pages 377-390
  3. Larghi P., Viola A., Molon B. Analysis of T cell activation by confocal microscopy. T cell differentiation: methods and protocols. 1514:63-81.PMID: 27787792
  4. Molon B, Calì B, Viola A. T Cells and Cancer: How Metabolism Shapes Immunity. Front Immunol. 2016 Feb 1;7:20. doi: 10.3389/fimmu.2016.00020
  5. Calì B, Ceolin S, Ceriani F, Bortolozzi M, Agnellini AH, Zorzi V, Predonzani A, Bronte V, Molon B, Mammano F. Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury. Oncotarget. 2015 Apr 30;6(12):10161-74. LAST NAME AND CORRESPONDING AUTHOR IF 6.354
  6. Sonda N, Simonato F, Peranzoni E, Calì B, Bortoluzzi S, Bisognin A, Wang E, Marincola FM, Naldini L, Gentner B, Trautwein C, Sackett SD, Zanovello P, Molon B, Bronte V. miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis. Immunity. 2013 June 27;38(6):1236-49. doi: 10.1016/j.immuni.2013.06.004. IF. 19.748
  7. Hickman HD, Reynoso GV, Ngudiankama BF, Rubin EJ, Magadán JG, Cush SS, Gibbs J, Molon B, Bronte V, Bennink JR, Yewdell JW. Anatomically restricted synergistic antiviral activities of innate and adaptive immune cells in the skin. Cell Host Microbe. 2013 Feb 13;13(2):155-68. doi: 10.1016/j.chom.2013.01.004. IF 10.34
  8. Viola A, Sarukhan A, Bronte V, Molon B. The pros and cons of chemokines in tumor immunology. Trends Immunol. 2012 Oct;33(10):496-504. doi: 10.1016/j.it.2012.05.007. IF 10.89
  9. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med. 2011 Sep 26;208(10):1949-62. doi: 10.1084/jem.20101956. CORRESPONDING AUTHOR. Evaluated and recommended by FACULTY OF 1000 IF 13.855
  10. Contento RL, Molon B, Boularan C, Pozzan T, Manes S, Marullo S, Viola A. CXCR4-CCR5: a couple modulating T cell functions. Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10101-6. doi: 10.1073/pnas.0804286105.

BARBARA MOLON

  • Assistant Professor: Immunology Section Department of Biomedical Sciences, University of Padova, Italy (since 2015)
  • Junior PI at the Venetian Institute of Molecular medicine, VIMM, Padova, Italy (since 2012)
  • Scientific collaboration with Dr. Bruno Silva-santos, Instituto de Medicina Molecular- Faculty of Medicine, University of Lisbon, Portugal (since 2010)
  • Degree of Specialist in Clinical Pathology, at University of Padova, Italy (2010)
  • Fellowship Oncological Venetian Institute, I.O.V., I.R.C.C.S., Padova, Italy (2010-2013)
  • Scientific collaboration with Dr. Santos Manes Broton at the National Center of Biotechnology of Madrid, (CNB/CSIC), Spain (2005)
  • Doctor of Biological Science, at University of Padova, Italy (2005)

Selected Awards

  • Harlan award, one award to the first author of the best paper, describing a research project performed in Italy and published in 2005 (Paris, 6-9 2006)
  • 4th edition Premio Manzin, best oral communication award (Marostica 2010)