Kerry S. Campbell, PhD

Kerry Campbell 2023
​​

This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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Professor

Director, Cell Culture Facility​

Co-Director, Immune Monitoring/Cell Sorting Facility

Lab Overview

NK cells constitute about 10-15% of the normal lymphocytes in human peripheral blood. They are important sentinels of the innate immune system that can detect and kill tumor cells and virus-infected cells, and produce cytokines, including interferon-γ and tumor necrosis factor-α. NK cells are regulated by a dynamic balance between positive and negative intracellular signals that are transduced from cell surface activating and inhibitory receptors. This makes them an ideal cellular model system to study signal transduction crosstalk. Our goal is to understand the molecular mechanisms by which NK cells selectively recognize and attack tumor cells in the body, and design therapeutic strategies that can enhance their responses in patients.

Killer cell immunoglobulin-like receptors (KIRs) are key regulators of human NK cell function that transduce a negative intracellular signal to suppress NK cell killing responses toward normal cells. We are studying the molecular mechanisms controlling the function and surface expression of KIRs. Recent work in collaboration with Dr. Heinrich Roder at FCCC used NMR analysis to detect structural changes in the cytoplasmic domain of an inhibitory KIR upon its interaction with the SHP-2 protein tyrosine phosphatase (Cheng et al., Structure 2019). Improved understanding of the regulation and molecular function of KIR should lead to therapeutic treatments to lower the NK cell activation threshold to more efficiently attack tumor cells and virus-infected cells.

In addition, we are also studying the contributions of NK, T, and myeloid cells in immune responses toward cancer. Multiparametric flow cytometry is being employed to study the phenotype and function of immune cells in the peripheral blood of cancer patients. Over the past decade, we have been studying cohorts of patients with renal cell carcinoma (MacFarlane et al., Cancer Immunol. Res. 2014), chronic lymphocytic leukemia (MacFarlane et al., Oncoimmunol. 2017), inflammatory breast cancer (Fernandez et al., Breast Cancer Res. 2020), multiple myeloma (Pazina et al., 2021), and acute myeloid leukemia (Zhigarev et al., Cancers 2022). These immune phenotyping studies have identified biomarkers with prognostic value and potential targets for immunotherapy. The work also provided the foundation for a collaborative co-PI project with a psychologist at FCCC, Dr. Carolyn Fang, to establish relationships between psychosocial functioning and immune phenotype in indolent non-Hodgkins Lymphoma (NHL) patients. NHL patients were chosen for study, because they can become particularly stressed during their untreated indolent stage of disease. Exciting preliminary data indicate a strong association between increased stress or anxiety and changes in monocyte subpopulations, as well as reduced expression of some common NK cell activating receptors in patients with depressive symptoms.

Immunotherapies that enhance NK cell function to treat cancer are also under study, including therapeutic antibodies targeting PD-1, KIR, and SLAMF7. We are characterizing mechanisms by which these and other antibodies enhance NK cell antitumor responses through blocking inhibitory pathways, co-stimulating, or initiating antibody dependent cellular cytotoxicity (ADCC) responses. For example, our mechanistic studies have revealed that the therapeutic anti-SLAMF7 antibody, elotuzumab, triggers both ADCC and co-stimulatory signaling in NK cells toward multiple myeloma (Pazina et al., Oncoimmunol. 2017 and Cancer Immunol. Res. 2019). Furthermore, previous collaborative studies with Dr. Yuri Sykulev (Kimmel Cancer Center, Thomas Jefferson University, Philadelphia) studying the roles of integrins in ADCC responses (Steblyanko et al., 2015) spawned a co-PI project to perform basic mechanistic analysis of how nano- and micro-clustering of FcγRIIIa (CD16), integrins, and inhibitory receptors influences ADCC responses. Results from these studies are expected to substantially advance our understanding of basic mechanisms of NK cell receptor function and lead to improved designs of anti-tumor antibodies.

Upon gaining significant experience in immune phenotyping studies of cancer patients, Dr. Campbell became Co-Director of the FCCC Immune Monitoring/Cell Sorting Facility in 2016, where he designs, guides, and interprets flow cytometry-based correlative studies for ongoing immunotherapy clinical trials at Fox Chase and collaborating outside institutions. These studies have benefited from the rich clinical resources at FCCC and involve collaborations with a vast array of clinicians. One study with Dr. Namrata Vijayvergia (Dept. of Hematology/Oncology) found that patients with grade 3 neuroendocrine neoplasms treated with pembrolizumab had improved PFS if their peripheral blood pretreatment had higher peripheral T cell counts, lower TIM-3 expression on T cells, and lower activation state of NK cells and naïve T cells (MacFarlane et al., Cancer Immunol. Immunother. 2021). Another clinical trial in collaboration with Dr. Elizabeth Plimack (Dept. of Hematology/Oncology) tested the effect of guadecitabine + atezolizumab in bladder cancer patients and found longer survival in patients with higher baseline TCF1 expression and greater induction of HLA-DR and NKG2D on peripheral blood T and NK cells (Jang et al., Clin. Cancer Res. 2023). Also, in collaboration with Dr. Matthew Zibelman (Dept. of Hematology/Oncology), a clinical trial testing the impact of interferon-gamma + nivolumab in patients with advanced solid tumors found that shorter duration of treatment was associated with lower baseline counts of CD4+ T cells in peripheral blood and higher induction of PD-L1 expression on monocytes after initiation of treatment (Zibelman et al., Nature Commun. 2023).

  • Campbell Slide NK-92 CD16 Synapse

    A conjugate pair of a NK-92.CD16 cell and a 721.221 tumor cell that has been pre-treated with the anti-CD20 antibody rituximab, fixed and immunostained, then imaged with a Leica TSC Sp8 advanced confocal microscope (left image). Rituximab bound to CD20 on the tumor cell is recognized by the NK cell through the Fc gamma receptor CD16 (green), which concentrates on the NK cell surface at the interface between the two cells. F-Actin (blue), concentrates inside the NK cell directly adjacent to the tumor cell, helping to form the wide lamella-like interface between the two cells. Confocal microscopy was used to collect information about fluorescent signal at focused points along the height of the cell, which was then converted into a transverse slice of the interface (right image, taken from white box). From here it can be observed that CD16 accumulates primarily at a central spot within the interface where the actin accumulation is less dense compared to the periphery. This central spot of hypo-dense actin provides an open area at the interface where cytolytic degranulation can occur.

  • Campbell Slide NK-92 Polarization

    A conjugate pair of a NK-92.CD16 cell and a 721.22 tumor cell, fixed and immunostained, then imaged with a Leica TSC SP8 advanced confocal microscope. F-Actin (blue) can be seen throughout the cell but is concentrated heaviest in the NK cell directly adjacent to the tumor cell, where it helps produce a wide lamella-like interface with the tumor cell. The microtubule organizing center (MTOC) of the cell, here shown through pericentrin (green), is polarized towards the interface upon conjugate formation. As the nexus of intracellular trafficking in the cell, the migration of the MTOC also draws cytolytic vesicles to the interface as well, here shown through perforin (yellow), allowing for directed degranulation and killing of the tumor cell.

  • Campbell Lab 2019

    Campbell Lab 2019 (left to right): Top - Dmitry Zhigarev, Kerry Campbell, Ph.D., Irina Shchaveleva; Bottom - Alexander MacFarlane, Ph.D., Kimberly Branigan Colby, Judy Fang.

  • Campbell Lab 2017 (#2) (left to right): Kimberly Branigan Colby, Chun Zhou, PhD, Sanjna Shelukar, Alexander MacFarlane, PhD, Kerry Campbell, PhD, Dmitry Zhigarev, Tatiana Pazina; Sitting: Irina Shchaveleva

  • Campbell Lab 2017 (#1): Standing: Alexander MacFarlane, PhD, Dmitry Zhigarev, Kerry Campbell, PhD, Sanjna Shelukar, Tatiana Pazina; Sitting: Chun Zhou, PhD, Kimberly Branigan Colby, Irina Shchaveleva

  • Campbell Lab 2013 (#2) “Levitating” (left to right): Poliana Patah, MD, Jun Hasegawa, PhD, Alexander MacFarlane, PhD, Ashley James, PhD, Kerry Campbell, PhD, Tatiana Pazina, Amanda Purdy, PhD, Jennifer Oshinsky

  • Campbell Lab 2013 (#1) (left to right): Poliana Patah, MD, Jun Hasegawa, PhD, Alexander MacFarlane, PhD, Ashley James, PhD, Kerry Campbell, PhD, Tatiana Pazina, Amanda Purdy, PhD, Jennifer Oshinsky

  • Campbell Lab 2010 (left to right): Mowafaq Jillab, MD, Alexander MacFarlane, PhD, Amanda Purdy, PhD, Michael Brusilovsky, Margaret Joyce, PhD, Jennifer Oshinsky, Kerry Campbell, PhD, Nicholas Rodin

     

    Educational Background

    • Independent Member, Basel Institute for Immunology, Basel, Switzerland, 1998
    • Post-Doctoral Training, National Jewish Research Center, Denver, CO, 1992
    • PhD, Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA, 1988
    • BS, Pharmacy, University of Toledo, Toledo, OH, 1983

    Memberships

    • Standing Member, NIH Innate Immunity and Inflammation (III) Study Section, 2013–2017
    • Member, American Association of Immunologists
    • Member, American Association for the Advancement of Science
    • Member, Society for Natural Immunity
    • Member, American Association of Cancer Research
    • Member, FCCC Facility Advisory Committees and Facilities Parent Oversight Committee
    • Review Editor, Frontiers in NK and Innate Cell Biology, and Cancer Immunity and Immunotherapy

    People

    Research Interests

    Human natural killer (NK) cells and cancer

    • Molecular mechanisms regulating the function of receptors on NK cells
    • Profiling the phenotype and function of immune cells in cancer patients
    • Therapeutic antibodies to target antitumor responses by human NK cells, including ADCC

    Lab Overview

    The Campbell lab has a longstanding interest in the mechanisms by which an assortment of germline-encoded receptors on the surface of human natural killer (NK) cells control their cytotoxic response toward tumor cells and to determine how that information might be exploited therapeutically to benefit cancer patients. In the course of over 25 years of independent research at Fox Chase Cancer Center, the group has gained extensive expertise in the culture and genetic manipulation of primary human NK cells and NK cell lines, as well as techniques in protein biochemistry, signaling, and molecular biology to study these intriguing innate immune cells. More recently, the team has focused extensively on clinical and translational research, in which they have studied the phenotype and function of NK, T, and myeloid cells in patients with various cancers and the mechanisms of action of several immunotherapeutic agents that exploit NK cell function in cancer patients.

    Lab Description

    Natural killer (NK) cells constitute about 10-15% of the normal lymphocytes in human peripheral blood. They are important sentinels of the innate immune system that can detect and kill tumor cells and virus-infected cells, and produce cytokines, including interferon-γ and tumor necrosis factor-α. NK cells are regulated by a dynamic balance between positive and negative intracellular signals that are transduced from cell surface activating and inhibitory receptors. This makes them an ideal cellular model system to study signal transduction crosstalk. Our goal is to understand the molecular mechanisms by which NK cells recognize and attack abnormal cells in the body, but are tolerant toward normal cells. This knowledge should lead to therapeutic strategies that can enhance NK cell responsiveness toward tumors and viruses in patients.

    Killer cell immunoglobulin-like receptors (KIRs) are key regulators of human NK cell function. KIRs bind major histocompatibility complex class I (MHC-I) molecules on the surfaces of all healthy normal cells in the body. Upon detecting MHC-I, KIRs transduce a negative intracellular signal that suppresses NK cell killing responses. In this way, the inhibitory signal derived when KIR detect MHC-I is important for establishing tolerance toward normal cells. Many abnormal tumor cells and virally infected cells eliminate MHC-I expression, however, which abolishes the KIR negative signals and releases the NK cells to specifically attack only these abnormal cells and eliminate them from the body. We are studying the molecular mechanisms controlling the function and surface expression of KIRs. Recent work in collaboration with Dr. Heinrich Roder at FCCC used NMR analysis to detect structural changes in the cytoplasmic domain of an inhibitory KIR upon its interaction with the SHP-2 protein tyrosine phosphatase (Cheng et al., Structure 2019). Improved understanding of the regulation and molecular function of KIR should lead to therapeutic treatments to lower the NK cell activation threshold to more efficiently attack tumor cells and virus-infected cells.

    In addition, we are also studying the contributions of NK cells in immune responses toward cancer.  Multiparametric flow cytometry is being employed to study the phenotype and function of NK cells in the peripheral blood of cancer patients.  Over the past decade, we have been studying cohorts of patients with renal cell carcinoma (MacFarlane et al., Cancer Immunol. Res. 2014), chronic lymphocytic leukemia (MacFarlane et al., Oncoimmunol. 2017), inflammatory breast cancer (Fernandez et al., Breast Cancer Res. 2020), multiple myeloma (Pazina et al., 2021), and acute myeloid leukemia (Zhigarev et al., in preparation). These immune phenotyping studies have identified biomarkers with prognostic value and potential targets for immunotherapy.   The work also provided the foundation for a collaborative co-PI project with a psychologist at FCCC, Dr. Carolyn Fang, to establish relationships between psychosocial functioning and immune phenotype in indolent non-Hodgkins Lymphoma (NHL) patients. NHL patients were chosen for study, because they can become particularly stressed during their untreated indolent stage of disease. Exciting preliminary data indicate a strong association between increased stress and reduced expression of some common NK cell activating receptors.

    Immunotherapies that enhance NK cell function to treat cancer are also under study, including therapeutic antibodies targeting PD-1, KIR, and SLAMF7.  We are characterizing mechanisms by which these and other antibodies enhance NK cell antitumor responses through blocking inhibitory pathways, co-stimulating, or initiating antibody dependent cellular cytotoxicity (ADCC) responses. For example, our mechanistic studies have revealed that the therapeutic anti-SLAMF7 antibody, elotuzumab, triggers both ADCC and co-stimulatory signaling in NK cells toward multiple myeloma (Pazina et al., Oncoimmunol. 2017 and Cancer Immunol. Res. 2019). Furthermore, previous collaborative studies with Dr. Yuri Sykulev (Kimmel Cancer Center, Thomas Jefferson University, Philadelphia) studying the roles of integrins in ADCC responses (Steblyanko et al., 2015) spawned a co-PI project to perform basic mechanistic analysis of how nano- and micro-clustering of FcγRIIIa (CD16), integrins, and inhibitory receptors influences ADCC responses.  Results from these studies are expected to substantially advance our understanding of basic mechanisms of NK cell receptor function and lead to improved designs of anti-tumor antibodies.

    Upon gaining significant experience in immune phenotyping studies of cancer patients, Dr. Campbell became Co-Director of the new FCCC Immune Monitoring Facility (IMF) in 2016, where he designs, guides, and interprets flow cytometry-based correlative studies for ongoing immunotherapy clinical trials at Fox Chase and collaborating outside institutions. These studies have benefited from the rich clinical resources at FCCC and involve collaborations with a vast array of clinicians.  The IMF is processing fresh blood samples from multiple clinical trials with the goals of identifying biomarkers that predict responses to immunotherapies in patients and discovering potential targets for additional immune therapy intervention.  Accordingly, T-cell lymphoma patients treated with the PD-1 blocking antibody, pembrolizumab, had better progression free survival (PFS) if they started therapy with a higher relative percentage of CD4+ T lymphocytes in peripheral blood (Barta et al., Clin. Lymphoma Myeloma Leuk. 2019).  Another study with Vijayvergia (Dept. of Hematology/Oncology) found that patients with grade 3 neuroendocrine neoplasms treated with pembrolizumab had improved PFS if their peripheral blood pretreatment had higher peripheral T cell counts, lower TIM-3 expression on T cells, and lower activation state of NK cells and naïve T cells (MacFarlane et al., Cancer Immunol. Immunother. 2021).

    Misc

    Former staff members

    Sam Zahroun
    Dmitry Zhigarev
    Bryn Queeley
    Sam Zahroun
    Sei-ichi Yusa, PhD
    George Hii, B.S.
    Tracey L. Catina-Hughes, B.S.
    Akiko Kikuchi-Maki, PhD
    Nikolay Gresko, MD, PhD
    Diana A. Alvarez Arias, PhD
    Yingying Chen, MD, PhD, SM
    S. M. Shahjahan Miah, PhD
    Margaret M. Joyce, PhD
    Nicholas Rodin, B.S.
    Jennifer Oshinsky, B.S.
    Michael Brusilovsky, PhD
    Mowafaq Jillab, M.D.
    Jun Hasegawa, PhD
    Amanda K. Purdy, PhD
    Poliana Patah, M.D., Ph.D.
    Anna Thum, B.S.
    Ashley Mentlik James, Ph.D.
    Mohammed Haseebuddin, M.D.
    Andres F. Correa, M.D.
    Tatiana Pazina, Ph.D.
    Kimberly Colby, B.S.
    Judy Fang, B.S.

    Selected Publications

    Zhigarev, D., Varshavsky, A., MacFarlane IV, A.W., Jayaguru, P., Barreyro, L., Khoreva, M., Dulaimi, E., Nejati, R., Drenberg, C., and Campbell, K.S. (2022) Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology. Cancers, 14:3352. PMCID: 9320805

    Maskalenko N.A., Zhigarev D.,Campbell K.S., Harnessing natural killer cells for cancer immunotherapy: Dispatching the first responders. Nat Rev Drug Discov, 2022. https://www.ncbi.nlm.nih.gov/pubmed/35314852.

    Pazina, T., MacFarlane IV, A.W., Bernabei, L., Dulaimi, E., Bezman, N.A., Robbins, M.D., Ross, E.A., Campbell, K.S.*, and Cohen, A.D.* (2021) Relationships between NK cell phenotype and disease progression in multiple myeloma patients. Cancers 13:226. PMCID: 7827733. *Corresponding authors

    Belnoue, E., Leystra, A.A., Carboni, S., Cooper, H.S., Macedo, R., Harvey, K.N., Colby, K.B., Campbell, K.S., Vanderveer, L.A., Clapper, M.L., and Derouazi, M. (2021) Novel protein-based vaccine against self-antigen reduces the formation of sporadic colon adenomas in mice. Cancers, 13:845. PMCID: 7923075.

    MacFarlane 4th, A.W., Yeung, H.-M., Alpaugh, R.K., Dulaimi, E., Engstrom, P.F., Dasari, A., Campbell, K.S.*, and Vijayvergia, N.* (2021) Impacts of Pembrolizumab Therapy on T and NK cells in Patients with High-grade Neuroendocrine Neoplasms. Cancer Immunol. Immunother., in press. *Corresponding authors

    Francescone, R., Vendramini-Costa, D.B., Franco-Barraza, J., Wagner, J., Muir, A., Lau, A.N., Gabitova, L., Pazina, T., Gupta, S., Luong, T., Shah, N., Rollins, D., Malik, R., Thapa, R., Restifo, D., Zhou, Y., Cai, K.Q., Hensley, H.H., Tan, Y., Kruger, W.D., Devarajan, K., Balachandran, S., Klein-Szanto, A.J., El-Deiry, W.S., Vander Heiden, M.G., Peri, S., Campbell, K.S., Astsaturov, I., and Cukierman, E. (2021) Netrin G1/NGL-1 axis promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression. Cancer Discovery 11:446-479. PMCID: 7858242.

    Fernandez, S.V., MacFarlane IV, A.W., Jillab, M., Arisi, M.F., Yearley, J., Annamalai, L., Alpaugh, R.K., Cristofanilli, M., and Campbell, K.S. (2020) Immune phenotype of patients with stage IV metastatic inflammatory breast cancer. Breast Cancer Res., 22:134. PMCID: 7709446.

    Cheng, H., Schwell, V., Curtis, B.R., Fazlieva, R., Roder, H., and Campbell, K.S. (2019) Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2. Structure, 27:639-650. PMCID: 6447435.

    Kundu, K., Ghosh, S., Sarkar, R., Edri, A., Brusilovsky, M., Gershoni-Yahalom, O., Yossef, R., Shemesh, A., Soria, J.C., Lazar, V., Joshua, B.Z., Campbell, K.S., Elkabets, M., and Porgador, A. (2019) Inhibition of the NKp44-PCNA Immune Checkpoint Using a mAb to PCNA. Cancer Immunol. Res., 7:1120-1134. PMCID: 7233522.

    Pazina, T., James, A.M., Colby, K.B., Yang, Y., Gale, A., Jhatakia, A., Kearney, A., Bezman, N.A., Graziano, R.F., Robbins, M.D., Cohen, A.D., and Campbell, K.S. (2019) Enhanced SLAMF7 homotypic interactions by elotuzumab improves NK cell killing of multiple myeloma. Cancer Immunol. Res., 7:1633-1646. PMCID: 6774869.

    Wagner, J., Kline, C.L., Zhou, L.L., Campbell, K.S., MacFarlane 4th, A.W., Olszanski, A.J., Cai, K.Q., Hensley, H.H., Ross, E.A., Ralff, M.D., Zloza, A., Chesson, C.B., Newman, J.H., Kaufman, H., Bertino, J., Stein, M., El-Deiry, W.S. (2018) Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. Journal of Clinical Investigation, 128(6):2325-38, 2018. PMCID: 5983321... Expand

    Additional Publications

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    This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
    Learn more about Research Volunteering.