HARNESSING THE IMMUNE SYSTEM TO FIGHT CANCER
Our laboratory is interested in understanding the link between T cell metabolism and immunity in cancer. Cancer immunotherapy has been one of the major breakthroughs of cancer treatments. However, despite the impressive results, the incidence of cancer is still raising and the response is heterogeneous. Thus, there is a critical need to develop new approaches to enhance response in patients who fail immunotherapy.
In the fight against cancer, CD8+ T cells are the soldiers of the immune system which destroy tumor cells. However, they become progressively dysfunctional and no longer able to control tumor outgrowth. This phenomenon is named “T cell exhaustion”.
Our group has recently found one of the mechanisms by which the tumor microenvironment drives CD8+ T cell exhaustion by depleting nutrients that are fundamental for sustaining their activity. We are now studying how this ‘starvation’ impacts the functionality of T cells. How can T cells switch between different source of energy to fuel their anti-tumor activity? Our lab is exploring new ways to engineer CD8+ T cells to improve their metabolic fitness in order to improve immunotherapeutic treatment of cancer.
- Manzo T, Nezi L, Prentice B, Raman A, Dwyer CK, Bartolacci C, Reyzer M, Kim M, Scaglioni P, Tucci S, Wargo J, Draetta G. Lipid accumulation during PDAC progression drives CD8 T cell dysfunction. In preparation.
- Gopalakrishnan V*, Nezi L*, Spencer C*, Reuben A, Andrews M, Karpinets T, Prieto P, Vicente D, Hoffman K, Cogdill A, Zhao L, Hudgens C, Hutchinson D, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy S, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall E, Rezvani K, Alousi A, Chemaly R, Shelburne S, Vence L, Okhuysen P, Jensen V, Swennes A, McAllister F, Marcelo Riquelme Sanchez E, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman J, Haydu L, Burton E, Gardner J, Sirmans E, Hu J, Lazar A, Tsuj ikawa T, Diab A, Tawbi H, Glitza I, Hwu WJ, Patel S, Woodman S, Amaria R, Davies M, Gershenwald J, Hwu P, Lee J, Zhang J, Coussens L, Cooper Z, Tetzlaff M, Futreal A, Daniel-MacDougall C, Ajami N, Petrosino J, Sharma P, Allison J, Jenq R & and Wargo J. Gut microbiome influences therapeutic response to PD-1 blockade in melanoma patients. Science, 2017.
- Nezi L, Te Boekhorst V, Terranova C, Manzo T, Carugo A, Petaccia De Macedo M, Villa F, Sarkar S, Akdemir KC, Chang Q, Inoue A, Puca F, Deribe Lissanu Y, Li Lin, Huang-Hobbs E, Garcia DA, Sobral M, Ho YW, Marchesini M, Reuben A, Viale A, Colla S, Chin L, Hawke DH, Herlyn M, Wargo JA, Davies MA, Lazar AJ, Rai K, Timothy Heffernan T, DePinho RA, Friedl P, and Giulio F. Draetta. NEK7-YAP axis drives collective cell invasion in melanoma. (Under revision).
- Manzo T, Sturmheit T, Basso V, Petrozziello E, Hess Michelini R, Freschi M, Protti MP, Schumacher T, Debets R, Swartz MA, Corti A, Bellone M, Mondino A. Alloreactive T cell-induced intratumoral TNF-a warrants therapeutic efficacy to TCR engineered T cells in the cure of solid tumors. Cancer Res, 2016.
- Del Bufalo F, Manzo T, Hoyos V, Yagyu S, Caruana I, Jacot J, Benavides O, Rosen D, Brenner MK. 3D modeling of human cancer: a PEG-fibrin hydrogel system to study the role of tumor microenviroment and recapitulate the in vivo effect of oncolytic adenovirus. Biomaterials, 2016.
- Sivakumaran S, Henderson S, Ward S, Sousa PS, Manzo T, Zhang L, Conlan T, Means TK, D'Aveni M, Hermine O, Rubio MT, Chakraverty R, Bennett CL. Depletion of CD11c⁺ cells in the CD11c.DTR model drives expansion of unique CD64⁺ Ly6C⁺ monocytes that are poised to release TNF-α. Eur J Immunol. 2016.
- Manzo T, Heslop HE, Rooney CM. Antigen-specific T cell therapies for cancer. Hum Mol Genet, 2015
- Platonova N, Manzo T, Mirandola L, Colombo M, Calzavara E, Vigolo E, Cermisoni GC, De Simone D, Garavelli S, Cecchinato V, Lazzari E, Neri A, Chiaramonte R. PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation. Genes Chromosomes Cancer, 2015
- Veliça P, Zech M, Henson S, Holler A, Manzo T, Pike R, Santos E Sousa P, Zhang L, Heinz N, Schiedlmeier B, Pule M, Stauss H, Chakraverty R. Genetic regulation of fate decisions in therapeutic T cells to enhance tumor protection and memory formation. Cancer Res, 2015
- D'Aveni M, Rossignol J, Coman T, Sivakumaran S, Henderson S, Manzo T, Santos e Sousa P, Bruneau J, Fouquet G, Zavala F, Alegria-Prévot O, Garfa-Traoré M, Suarez F, Trebeden-Nègre H, Mohty M, Bennett CL, Chakraverty R, Hermine O, Rubio MT. G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. Sci Transl Med, 2015
- Buchan SL*, Manzo T*, Flutter B, Rogel A, Edwards N, Zhang L, Sivakumaran S, Ghorashian S, Carpenter B, Bennett CL, Freeman GJ, Sykes M, Croft M, Al-Shamkhani A, Chakraverty R. OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. *Co-First author J Immunol, 2015
- Manzo T, Michelini RH, Sturmheit T, Basso V, Bellone M, Mondino A. Tumor-trageting vaccination instructs graft-vs.-tumor immune responses. Oncoimmunology, 2013.
- Hess Michelini R*, Manzo T*, Sturmheit T, Basso V, Rocchi M, Freschi M, Listopad J, Blankenstein T, Bellone M, Mondino A. Vaccine-instructed intratumoral IFN-regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation. *Co-First author. Cancer Res, 2013.
- Marangoni F, Murooka TT, Manzo T, Kim EY, Carrizosa E, Elpek NM, Mempel TR. The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity, 2013.
- Manzo T, Hess Michelini R, Basso V, Ricupito A, Chai JG, Simpson E, Bellone M, Mondino A. Concurrent allorecognition has a limited impact on posttransplant vaccination. J Immunol. 2011.
- Hess Michelini R, Freschi M, Manzo T, Jachetti E, Degl'Innocenti E, Grioni M, Basso V, Bonini C, Simpson E, Mondino A, Bellone M. Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors. Cancer Res. 2010.