Cancer Immunology Program
The Cancer Immunotherapy Program at CSB, directed by Mikael Pittet, PhD brings together different labs at MGH (Pittet, Pai, Miller, Weissleder) who conduct basic and translational research on the immune system and emphasize the use of in vivo systems biology and imaging approaches to interrogate how various immune components behave in complex environments.
Major goals are to (1) uncover key mechanisms regulating both adaptive immune cells (e.g. T cells, B cells) and innate immune cells (e.g. macrophages, neutrophils, dendritic cells); (2) identify new immuno-oncology therapies that stimulate antitumor immunity against a broader range of tumors.
These goals are motivated by increasing evidence that tumor microenvironments can accumulate a diversity of immune cell types, many of which control tumor progression and response to treatment.
Program members working within CSB maintain strong ties with local (MGH Research Institute, Harvard, MIT, Broad), national and international investigators, and currently focus on various cancer types including lung, pancreas, head and neck cancer and melanoma.
The growth of a tumor and its ability to progress and metastasize is influenced by a variety of host components, including various stomal and immune cells. Precisely how the microenvironment influences tumor outgrowth remains poorly understood. This Program utilizes recent advances in molecular imaging, nanoscale materials and gene profiling efforts to quantify and model cellular and molecular immune components of the tumor microenvironment. The approaches are aimed to discover fundamental aspects of immune responses to cancer and establish new paradigms for future translational efforts. Additionally, the Program investigates tumor-driven mechanisms that modulate immune cells in the entire body. This important considering that some tumors affect immune cell components well beyond the local tissue microenvironment and that immune cell subsets in various body compartment can regulate tumor cell dissemination and metastasis.
The first wave of immuno-oncology therapies has revolutionized cancer treatment by successfully demonstrating that enhancing antitumor T cell activity controls some cancers durably and provides impressive survival benefits. Considering that tumor microenvironments are home to diverse immune cell types, including cells other than T cells, it is a critical time to uncover whether additional immune components are relevant next generation immuno-oncology targets. This Program specifically explores ways for stimulating both adaptive and innate antitumor immunity, and methods for rationally identifying effective new drug combinations. The Program also uses new reporters and imaging tools to uncover how drugs affect immune cells in real time in vivo. By considering multiple immune cell types and examining drug response and resistance mechanisms, the Program aims to define new therapeutic interventions that stimulate immunity against a broader diversity of tumors and improve the quality of life of more patients. Targeting resistance barriers contributed by several tumor-associated host components may be particularly relevant for patients who resist T cell immune checkpoint blockade treatments.
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
Bill R, Deschler DG, Pittet MJ, Pai SI, Sadow PM, Park JC Diagnostic challenges and successful organ-preserving therapy in a case of secretory carcinoma of minor salivary glands. Cancer Rep (Hoboken). 2021;:e1491 - PMID: 34231337 - DOI: 10.1002/cnr2.1491
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CSB work is profiled in MGH Research Institute spotlight "Mass General Researchers Investigate the ‘Big Eaters’ of the Immune System: #MacrophageMonday"
Checking out checkpoints: Immune checkpoint blockers (ICBs) are designed to activate the immune system against cancer. These drugs can be extraordinarily effective in some patients but not in others. Now, Mikael Pittet and colleagues have used molecular imaging to track ICBs in real time within tumors. Their study, published in Science Translational Medicine, uncovers a mechanism of treatment resistance, which can be overcome with additional chemical modifications. See also: the Journal Cover illustrating the “Tug-of-war with anti-PD-1” and interview with the authors.