Nikhil Joshi, PhD
Research & Publications
Tumors exist within a complex tumor microenvironment that develops during the course of disease, but very little is known about how the microenvironment develops, or how the cells within the microenvironment impact the outcome of disease. This is particularly true of immune cells in the tumor microenvironment, which co-exist with tumor cells throughout development. Many immune cells in the tumor microenvironment (and in particular T cells that recognize tumor cells) are non-functional, although it remains unclear why or how they reached this state. Immunotherapies that can improve anti-tumor T cell function have demonstrated the remarkable ability to cause sustained tumor regression and extend the lifespans of some patients with advanced cancers for years. These results highlight the potential of immunotherapeutics, but expanding their benefits to most cancer patients will require a better understanding of how the tumor microenvironment impacts immune cell function, and how the microenvironment associated with advanced tumors developed during disease. My laboratory uses and develops complex genetically engineered mouse models (GEMMs) of cancer, with the aim of investigating these questions. We primarily focus on how cells of the immune system help shape the tumor microenvironment during disease development and how the tumor microenvironments associated with different cancer types affect anti-tumor T cells. The overall goal of our work is to identify key molecular mechanisms that contribute to disease progression and immune dysfunction and to target these mechanisms to improve disease outcomes for patients with advanced cancers.
Antigens, Differentiation, T-Lymphocyte; Carcinoma, Non-Small-Cell Lung; T-Lymphocytes, Helper-Inducer; Immunotherapy; Oncogenes; T-Lymphocytes, Cytotoxic; Genes, Tumor Suppressor; T-Lymphocytes, Regulatory; Tumor Microenvironment
Public Health Interests
- Novel Mouse Models for Cancer ImmunologyConnolly K, Fitzgerald B, Damo M, Joshi N. Novel Mouse Models for Cancer Immunology Annual Review Of Cancer Biology 2022, 6: 1-23. PMID: 36875867, PMCID: PMC9979244, DOI: 10.1146/annurev-cancerbio-070620-105523.
- Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responsesCui C, Wang J, Fagerberg E, Chen PM, Connolly KA, Damo M, Cheung JF, Mao T, Askari AS, Chen S, Fitzgerald B, Foster GG, Eisenbarth SC, Zhao H, Craft J, Joshi NS. Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses Cell 2021, 184: 6101-6118.e13. PMID: 34852236, PMCID: PMC8671355, DOI: 10.1016/j.cell.2021.11.007.
- A mouse model for the study of anti-tumor T cell responses in Kras-driven lung adenocarcinomaFitzgerald B, Connolly KA, Cui C, Fagerberg E, Mariuzza DL, Hornick NI, Foster GG, William I, Cheung JF, Joshi NS. A mouse model for the study of anti-tumor T cell responses in Kras-driven lung adenocarcinoma Cell Reports Methods 2021, 1: 100080. PMID: 34632444, PMCID: PMC8500377, DOI: 10.1016/j.crmeth.2021.100080.
- A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing anti-tumor immune responseConnolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, Hornick NI, Fitzgerald BL, Damo M, Kasmani MY, Cui C, Fagerberg E, Monroy I, Hutchins A, Cheung JF, Foster GG, Mariuzza DL, Nader M, Zhao H, Cui W, Krishnaswamy S, Joshi NS. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing anti-tumor immune response Science Immunology 2021, 6: eabg7836. PMID: 34597124, PMCID: PMC8593910, DOI: 10.1126/sciimmunol.abg7836.
- Inducible de novo expression of neoantigens in tumor cells and miceDamo M, Fitzgerald B, Lu Y, Nader M, William I, Cheung JF, Connolly KA, Foster GG, Akama-Garren E, Lee DY, Chang GP, Gocheva V, Schmidt LM, Boileve A, Wilson JH, Cui C, Monroy I, Gokare P, Cabeceiras P, Jacks T, Joshi NS. Inducible de novo expression of neoantigens in tumor cells and mice Nature Biotechnology 2020, 39: 64-73. PMID: 32719479, PMCID: PMC7854852, DOI: 10.1038/s41587-020-0613-1.
- The NINJA mouse: a novel model to study tissue-specific peripheral T cell toleranceDamo M, Joshi N. The NINJA mouse: a novel model to study tissue-specific peripheral T cell tolerance The Journal Of Immunology 2018, 200: 47.6-47.6. DOI: 10.4049/jimmunol.200.supp.47.6.
- A Modular Assembly Platform for Rapid Generation of DNA ConstructsAkama-Garren EH, Joshi NS, Tammela T, Chang GP, Wagner BL, Lee DY, Rideout III W, Papagiannakopoulos T, Xue W, Jacks T. A Modular Assembly Platform for Rapid Generation of DNA Constructs Scientific Reports 2016, 6: 16836. PMID: 26887506, PMCID: PMC4757859, DOI: 10.1038/srep16836.
- The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infectionDominguez C, Amezquita R, Guan T, Marshall H, Joshi N, Kleinstein S, Kaech S. The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection Journal Of Cell Biology 2015, 211: 2113oia258. DOI: 10.1083/jcb.2113oia258.
- Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell ResponsesJoshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, Robbins R, Crowley DM, Bronson RT, Jacks T. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses Immunity 2015, 43: 579-590. PMID: 26341400, PMCID: PMC4826619, DOI: 10.1016/j.immuni.2015.08.006.
- Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription FactorJoshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM. Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription Factor Immunity 2007, 27: 281-295. PMID: 17723218, PMCID: PMC2034442, DOI: 10.1016/j.immuni.2007.07.010.