Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Sckisel, Gail D.; Mirsoian, Annie; Minnar, Christine M.; Crittenden, Marka R.; Curti, Brendan D.; Chen, Jane Q.; Blazar, Bruce R.; Borowsky, Alexander D.; Monjazeb, Arta M.; Murphy, William J.

doi:10.1186/s40425-017-0235-4

Cited by 55 publications

(48 citation statements)

References 25 publications

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“…PSPEI-PAA administration in B16F10 tumor via peritumoral route initiates the antitumor immune response by maturating dendritic cells and in turn activating the cytotoxic T cells through T helper (Th) cells. The activated CTL kills the tumor [44,45]. From this, it can be assessed that the B16F10 lysate protein mediated activation of cytotoxic T cells in the splenocytes has led to killing of the B16F10 melanoma cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response against Melanoma Tumor

et al. 2018

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Malignant melanoma is a highly aggressive type of cancer that requires radical treatment strategies to inhibit the cancer cell progression and metastasis. In recent years, preclinical research and clinical trials on melanoma treatment have been considerably focused on the adjuvant-based immunotherapy for enhancing the immune response of innate immune cells against cancer cells. However, the clinical outcome of these adjuvant-based treatments is inadequate due to an improper delivery system for these immune activators to reach the target site. Hence, we developed a vaccine formulation containing tumor lysate protein (TL) and poly I:C (PIC) complexed with positively charged poly (sorbitol-co-polyethylenimine (PEI) (PSPEI). The resulting ionic PSPEI-polyplexed antigen/adjuvant (PAA) (PSPEI-PAA) nanocomplexes were stable at the physiological condition, are non-toxic, and have enhanced intracellular uptake of antigen and adjuvant in immature dendritic cells leading to dendritic cell maturation. In the murine B16F10 tumor xenograft model, PSPEI-PAA nanocomplexes significantly suppressed tumor growth and did not exhibit any noticeable sign of toxicity. The level of matured dendritic cells (CD80+/CD86+ cells) in the tumor draining lymph node of PSPEI-PAA treated tumor mice were enhanced and therefore CD8+ T cells infiltration in the tumor were enriched. Additionally, the cytotoxic T lymphocytes (CTLs) assay involving co-culturing of splenocytes isolated from the PSPEI-PAA-treated mice with that of B16F10 cells significantly revealed enhanced cancer killing by the TL-reactivated CTLs compared to untreated control mice bearing tumor. Therefore, we strongly believe that PSPEI-PAA nanocomplexes could be an efficient antigen/adjuvant delivery system and enhance the antitumor immune response against melanoma tumor in the future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response against Melanoma Tumor

et al. 2018

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“…PSPEI-PAA administration in B16F10 tumor via peritumoral route initiates the antitumor immune response by maturating dendritic cells and in turn activating the cytotoxic T cells through T helper (Th) cells. The activated CTL kills the tumor and also differentiates into memory cytotoxic T cells [41,42]. Memory cytotoxic T cells will reside in the spleen and any future encounter with tumor antigen will lead to antitumor immune response [42].…”

Section: Discussionmentioning

confidence: 99%

“…The activated CTL kills the tumor and also differentiates into memory cytotoxic T cells [41,42]. Memory cytotoxic T cells will reside in the spleen and any future encounter with tumor antigen will lead to antitumor immune response [42]. From this, it could be assessed that the cytotoxic T cells present in the splenocytes was activated by the lysate protein, thereby leading to the killing of the B16F10 melanoma cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response Against Melanoma Tumor

Rajendrakumar¹,

Mohapatra²,

Singh³

et al. 2018

Preprint

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Malignant melanoma is a highly aggressive type of cancer that requires radical treatment strategies to inhibit the cancer cell progression and metastasis. In recent years, preclinical research and clinical trials on melanoma treatment are considerably focused on the adjuvant-based immunotherapy for enhancing the immune response of innate immune cells against cancer cells. However, the clinical outcome of these adjuvant-based treatments are inadequate due to improper delivery system for these immune activators to reach the target site. Hence, we developed a vaccine formulation containing tumor lysate protein (TL) and poly I:C (PIC) complexed with positively charged poly (sorbitol-co- polyethylenimine (PEI)(PSPEI). The resulting ionic PSPEI-polyplexed antigen/adjuvant (PAA) (PSPEI-PAA) nanocomplexes were stable at the physiological condition, non-toxic and  enhanced intracellular uptake in immature dendritic cells. In murine B16F10 tumor xenograft model, PSPEI-PAA nanocomplexes significantly suppressed tumor growth and did not exhibit any noticeable sign of toxicity. Additionally, the cytotoxic T lymphocytes (CTLs) assay involving co-culturing of splenocytes isolated from the PSPEI-PAA-treated mice with that of B16F10 cells significantly revealed enhanced cancer killing by the TL-reactivated CTLs compared to untreated control mice bearing tumor. Therefore, we strongly believe that PSPEI-PAA nanocomplexes could be an efficient antigen/adjuvant delivery system and also enhance the antitumor immune response against melanoma tumor in the future clinical trials.

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“…This phenotype indicates a mixed population of effector CD8 + T cells (T E ) and effector memory CD8 + T cells (T EM ). In a prophylactic vaccination setting a T E /T EM phenotype is thought to be less effective compared to a predominant central memory CD8 + T cell (T CM ) phenotype due to their limited proliferation potential [ 43 ], however in a therapeutic setting with the continued persistence of OVA antigen in the tumor it is not unexpected that they express an activated effector phenotype and others have shown this to correlate with a higher level of PD-1 expression [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

An Archaeosome-Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Significantly Enhances Protection from Murine Melanoma

et al. 2017

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Archaeosomes constitute archaeal lipid vesicle vaccine adjuvants that evoke a strong CD8+ T cell response to antigenic cargo. Therapeutic treatment of murine B16-ovalbumin (B16-OVA) melanoma with archaeosome-OVA eliminates small subcutaneous solid tumors; however, they eventually resurge despite an increased frequency of circulating and tumor infiltrating OVA-CD8+ T cells. Herein, a number of different approaches were evaluated to improve responses, including dose number, interval, and the combination of vaccine with checkpoint inhibitors. Firstly, we found that tumor protection could not be enhanced by repetitive and/or delayed boosting to maximize the CD8+ T cell number and/or phenotype. The in vivo cytotoxicity of vaccine-induced OVA-CD8+ T cells was impaired in tumor-bearing mice. Additionally, tumor-infiltrating OVA-CD8+ T cells had an increased expression of programmed cell death protein-1 (PD-1) compared to other organ compartments, suggesting impaired function. Combination therapy of tumor-bearing mice with the vaccine archaeosome-OVA, and α-CTLA-4 administered concurrently as well as α-PD-1 and an α-PD-L1 antibody administered starting 9 days after tumor challenge given on a Q3Dx4 schedule (days 9, 12, 15 and 18), significantly enhanced survival. Following multi-combination therapy ~70% of mice had rapid tumor recession, with no detectable tumor mass after >80 days in comparison to a median survival of 17–22 days for untreated or experimental groups receiving single therapies. Overall, archaeosomes offer a powerful platform for delivering cancer antigens when used in combination with checkpoint inhibitor immunotherapies.

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Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Cited by 55 publications

References 25 publications

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response against Melanoma Tumor

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response against Melanoma Tumor

Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response Against Melanoma Tumor

An Archaeosome-Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Significantly Enhances Protection from Murine Melanoma

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