My laboratory performs a research program on the host immune response in vivo with the main goal to offer valuable new ways to combat cancer. We use various modalities, including in vivo imaging, to study where, when and how immune cells are produced, traffic, and mediate regulatory or effector functions. The studies make use of both genetic mouse models, which allow manipulations and analyses of mechanisms and causality, and human patient material, to ensure that the results are anchored in clinical correlates. This dual approach gives opportunities for discovery of novel contributions of the immune response to tumor progression, new biomarkers useful for diagnosis and prognosis, and novel targets for therapeutic intervention. Dr. Pittet directs Cancer Immunology Program at CSB and collaborates with several immunology programs at Harvard Medical School, Massachusetts General Hospital and Massachusetts Institute of Technology.
Kim J, Oh J, Peterson HM, Carlson JCT, Pittet MJ, Weissleder R TNIK Inhibition Has Dual Synergistic Effects on Tumor and Associated Immune Cells. Adv Biol (Weinh). 2022;6(8):e2200030 - PMID: 35675910 - PMCID: PMC9398996 - DOI: 10.1002/adbi.202200030
Ko J, Wilkovitsch M, Oh J, Kohler RH, Bolli E, Pittet MJ, Vinegoni C, Sykes DB, Mikula H, Weissleder R, Carlson JCT Spatiotemporal multiplexed immunofluorescence imaging of living cells and tissues with bioorthogonal cycling of fluorescent probes. Nat Biotechnol. 2022;:ePub - PMID: 35654978 - DOI: 10.1038/s41587-022-01339-6
Pfirschke C, Zilionis R, Engblom C, Messemaker M, Zou AE, Rickelt S, Gort-Freitas NA, Lin Y, Bill R, Siwicki M, Gungabeesoon J, Sprachman MM, Marquard AN, Rodell CB, Cuccarese MF, Quintana J, Ahmed MS, Kohler RH, Savova V, Weissleder R, Klein AM, Pittet MJ Macrophage-targeted therapy unlocks antitumoral crosstalk between IFN𝛾-secreting lymphocytes and IL12-producing dendritic cells. Cancer Immunol Res. 2021;10(1):40-55 - PMID: 34795032 - DOI: 10.1158/2326-6066.CIR-21-0326
Ho WW, Gomes-Santos IL, Aoki S, Datta M, Kawaguchi K, Talele NP, Roberge S, Ren J, Liu H, Chen IX, Andersson P, Chatterjee S, Kumar AS, Amoozgar Z, Zhang Q, Huang P, Ng MR, Chauhan VP, Xu L, Duda DG, Clark JW, Pittet MJ, Fukumura D, Jain RK Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy. Proc Natl Acad Sci U S A. 2021;118(45):ePub - PMID: 34725151 - PMCID: PMC8609309 - DOI: 10.1073/pnas.2105323118
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In vitro studies often do not reliably predict the behavior of cells in vivo. Therefore our goals are: (a) to study cellular players directly in situ by means of appropriate bioimaging technologies, (b) to quantify and model information obtained by bioimaging, (c) to develop approaches for comprehensive investigation of various cell types in defined microenvironments. In cancer, a number of immune and nonimmune cell types respond to tumor stimuli and exhibit complex regulatory or effector functions, for example through cell-cell contact and/or secretion of soluble factors. We use recent advances in in vivo imaging to yield new insights into the biology of host cells with the ultimate goal to quantify cellular responses in vivo. As detailed below, we have focused our efforts on the study of T cell responses (anti-tumor CTL and suppressor Treg cells) and monocyte responses (monocyte subsets with distinct inflammatory potential and their lineage descendants).
Adaptive immune cells
T cells are specialized to recognize cells infected with intracellular pathogens or transformed cells expressing tumor-associated antigens. Cytotoxic T cells (CTL) execute their effector functions during direct physical interactions with their targets, which include release of lytic granules and secretion of cytokines. In contrast other T cells such as T regulatory (Treg) cells mediate dominant suppressive functions and can prevent the activity of CTL and other effector cells. Our understanding of how immune functions are regulated and integrated in vivo at the cellular level is, to a large extent, still speculative. We are studying how Treg cells repress CTL responses in vivo, and whether Treg cell-mediated tolerance can be reversed in therapy.
Innate immune cells
Mononuclear phagocytes exert crucial functions as scavengers and can trigger or regulate immune responses. Recent studies indicate that monocytes - the precursors of macrophages and dendritic cells - comprise separate subsets that 'commit' to specific functions. The activity of these subsets in vivo is largely unknown. We are studying tissue tropism, cellular differentiation and role in immunity of monocyte subsets in various inflammatory conditions. We are also testing whether these cells are potential targets in therapy.