Gail Sckisel

Immunoediting and antigen loss: overcoming the achilles heel of immunotherapy with antigen non-specific therapies.

Published in Frontiers in Oncology

Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes...

NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype.

Published in The Journal of Immunology

Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, inc...

Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immun...

Published in Blood

Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse ...

Specificity may be overrated in cancer immunotherapy: Getting to know the nonspecific side of memory T Cells.

Published in OncoImmunology

For a long time, cancer immunotherapy has focused on the induction of tumor-specific T cell-mediated immune responses. Now, a mounting body of evidence indicates that efficient anticancer immune responses also rely on innate immunity. Tietze et al. have recently elucidated an antigen-nonspecific role for memory CD8(+) T cells in cytokine-based canc...

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine...

Published in Clinical Cancer Research

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine m...

Published in OncoImmunology

The role of antigen-specific and non-specific immunotherapy in the treatment of cancer.

Published in Journal of Immunotoxicology

Immunotherapy in the treatment of cancer is increasing, particularly with the recent FDA approval of sipuleucel-T and ipilimumab. The efficacy of anti-tumor immunotherapies has been modest compared to their theoretical and pre-clinical promise. This review evaluates the promise and pitfalls of immunotherapy and highlight some of the obstacles to im...

Bystander activation and anti-tumor effects of CD8+ T cells following Interleukin-2 based immunotherapy is independent o...

We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated" (CD8(+)CD44high) T cells displaying a CD25(-)NKG2D(+) phenotype in a cytokine dependent manner, which were responsible for the a...

Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immu...

Published in Cancer Immunology Immunotherapy

We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of...

Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice...

Published in Journal of Experimental Medicine

Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) ...

Influenza infection results in local expansion of memory CD8(+) T cells with antigen non-specific phenotype and function...

Published in Clinical & Experimental Immunology

Primary viral infections induce activation of CD8(+) T cells responsible for effective resistance. We sought to characterize the nature of the CD8(+) T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8(+) T cells exhibiting ...

Increased antitumor effects using IL-2 with anti-TGF-β reveals competition between mouse NK and CD8 T cells.

Published in The Journal of Immunology

Because of increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL-2 with Abs to neutralize TGF-β, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater antitumor effects. These were correlated with significant increases in the numbers and functionali...

Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity.

Published in Immunity

Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby in...

Antigen-specific versus antigen-nonspecific immunotherapeutic approaches for human melanoma: the need for integration fo...

Published in International Reviews of Immunology

Due to its immunogenecity and evidence of immune responses resulting in tumor regression, metastatic melanoma has been the target for numerous immunotherapeutic approaches. Unfortunately, based on the clinical outcomes, even the successful induction of tumor-specific responses does not correlate with efficacy. Immunotherapies can be divided into an...