Melanoma-induced suppression of tumor antigen-specific T cell expansion is comparable to suppression of global T cell expansion

Russ, Andrew; Xu, Kyle; Wentworth, L.; Alam, Shabnam; Meyers, Justin V.; Macklin, Michael D.; Rakhmilevich, Alexander L.; Rajamanickam, Victoria; Suresh, M.; Cho, Clifford S.

doi:10.1016/j.cellimm.2011.06.011

Cited by 12 publications

(21 citation statements)

References 15 publications

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“…Importantly, this model employed aggressive in vitro stimulation of effector and memory T cell populations prior to adoptive transfer; consequently, it is possible that this preparative regimen effectively enriched homogenous populations of acutely activated effector T cells in both experimental groups, diluting any potential therapeutic benefit that memory T cells may inherently offer. We previously described the selection of B16F10 melanoma cell line clones stably transfected to express very low and poorly immunogenic levels of the LCMV epitope peptide GP33 (B16GP33) [19]. By rendering GP33 a novel tumor antigen and harvesting effector or memory phenotype GP33-specific CD8+ T cells from mice 8 or >30 days after LCMV infection, respectively, our model enables us to precisely control the phenotype of adoptively transferred tumor antigen-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

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Memory T cells are uniquely resistant to melanoma-induced suppression

Wentworth

Meyers

Alam

et al. 2012

Cancer Immunol Immunother

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We have previously observed that in vivo exposure to growing melanoma tumors fundamentally alters activated T cell homeostasis by suppressing the ability of naïve T cells to undergo antigen-driven proliferative expansion. We hypothesized that exposure of T cells in later stages of differentiation to melanoma would have similar suppressive consequences. C57BL/6 mice were inoculated with media or syngeneic B16F10 melanoma tumors 8 or 60 days after infection with lymphocytic choriomeningitis virus (LCMV), and splenic populations of LCMV-specific T cells were quantified using flow cytometry 18 days after tumor inoculation. Inoculation with melanoma on post-infection day 8 potentiated the contraction of previously activated T cells. This enhanced contraction was associated with increased apoptotic susceptibility among T cells from tumor-bearing mice. In contrast, inoculation with melanoma on post-infection day 60 did not affect the ability of previously established memory T cells to maintain themselves in stable numbers. In addition, the ability of previously established memory T cells to respond to LCMV challenge was unaffected by melanoma. Following adoptive transfer into melanoma-bearing mice, tumor-specific memory T cells were significantly more effective at controlling melanoma growth than equivalent numbers of tumor-specific effector T cells. These observations suggest that memory T cells are uniquely resistant to suppressive influences exerted by melanoma on activated T cell homeostasis; these findings may have implications for T cell–based cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…To test LCMV-specific memory T cell responses, LCMV-immune mice were infected with 10 6 PFU clone 13 strain LCMV by intravenous injection. Mice were also inoculated with 10 6 B16GP33 cells, previously generated in our laboratory by stable transfecting B16F10 cells to express low levels of the LCMV epitope peptide GP33 [19]. …”

Section: Methodsmentioning

confidence: 99%

Memory T cells are uniquely resistant to melanoma-induced suppression

Wentworth

Meyers

Alam

et al. 2012

Cancer Immunol Immunother

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“…The B16GP33 cell line was prepared as previously described (10,11). Briefly, B16F10 cells were transfected with a plasmid containing genes for the class I MHC-restricted LCMV surface glycoprotein GP33 and G418 resistance, and the resulting stably transfected cell line was selected by G418 resistance.…”

Section: Methodsmentioning

confidence: 99%

CTLA-4 Blockade Plus Adoptive T-Cell Transfer Promotes Optimal Melanoma Immunity in Mice

Mahvi

Meyers

Tatar

et al. 2015

Journal of Immunotherapy

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Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T cell populations (e.g., CTLA-4 blockade-mediated checkpoint inhibition) or introduce exogenously-prepared tumor-specific T cell populations (e.g., adoptive cell transfer). Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and non-lymphodepletional adoptive cell transfer could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, adoptive cell transfer, or combination immunotherapy of CTLA-4 blockade with adoptive cell transfer. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, as well as a stronger systemic immune responses reflected by more potent tumor antigen-specific T cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with non-lymphodepletional adoptive cell transfer may promote additive endogenous and exogenous T cell activities that enable greater therapeutic efficacy in the treatment of melanoma.

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“…This effect appears to be mediated by increased susceptibility of activated T cells to apoptotic cell death [18]. The magnitude of this suppression is proportional to the extent of tumor burden; moreover, this influence is exerted in a globally non-specific manner that affects tumor antigen-specific T cells to the same degree as non-tumor antigen-specific T cells [19]. These observations indicate that the presence of cancer fundamentally alters the homeostasis of newly activated T cells; indeed, we have found that the ability of mice to generate new MPEC is markedly impaired in the presence of melanoma tumors [18].…”

Section: Introductionmentioning

confidence: 99%