Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy

Abstract

The ability of immune-based cancer therapies to elicit beneficial CD8+ CTL is limited by tolerance pathways that inactivate tumor-specific CD4 helper T cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 helper T cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8+ CTL priming so long as the cognate epitopes are linked via presentation on the same dendritic cell. Here, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that not only provide help via the above-mentioned classical linked pathway, but also provide non-linked help that facilitates CTL function in T cells not directly responding to cognate antigen. We found that engagement of tumor-unrelated CD4 helper T cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual-costimulated helper cells are themselves helped by a CD134+ cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B+ effector CD8 T cells and a reciprocal decrease in Foxp3+CD4+ cell frequency. Notably, the tumor-unrelated CD4 helper T cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the anti-tumor response.

Regulatory T Cells and Cancer: A Two-Sided Story

“…Similarly, ablation of LAG-3, one of the effector molecules expressed on Treg cell surface, resulted in increased CD8 + T cell response to tumor antigen (Grosso et al, 2007;Goldberg & Drake, 2011). Also, costimulation with CD4 helper function mediated by CD134 and CD137 increases CTL infiltration and reduces Tregs in B16 melanoma (Mittal et al, 2015). Given the expression of immune suppressing ligands beyond Treg lineage, it remains to be determined what is the proportion of Treg-bound immune modulatory molecules that contributes to suppression of anti-tumor immunity.…”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…The second unusual feature of dual costimulated CD4 T cells is that they can provide help not only to CD8 T cells responding to antigen presented by the same APC (linked help [126][127][128]) but also elicit CTL function in T cells not actively responding to cognate antigen (nonlinked help [118,129,130]). These helper effects are at least partially mediated through the secre-future science group Cytokines & metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy Review tion of IL-2 and IFN-γ by the dual costimulated CD4 T cells [118,129,130].…”

“…These helper effects are at least partially mediated through the secre-future science group Cytokines & metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy Review tion of IL-2 and IFN-γ by the dual costimulated CD4 T cells [118,129,130]. Given that antigen cross-presentation by dendritic cells is biased toward highly abundant antigens [30,131], this nonlinked helper pathway might engage CD8 + CTL specific for less abundant tumor epitopes and thus increase the overall breadth of the antitumor response, and perhaps even target tumor variants that lack dominant epitopes.…”

“…Given that antigen cross-presentation by dendritic cells is biased toward highly abundant antigens [30,131], this nonlinked helper pathway might engage CD8 + CTL specific for less abundant tumor epitopes and thus increase the overall breadth of the antitumor response, and perhaps even target tumor variants that lack dominant epitopes. To test the ability of dual costimulated CD4 T cells capable of providing both linked and nonlinked help to boost therapeutic efficacy, mice bearing B16 melanomas were immunized with an MHC class II-restricted helper peptide along with dual costimulation [130]. Importantly, the helper peptide was foreign and not expressed by the tumor, thus bypassing the issue that tumor-specific CD4 T cells are often tolerant [106,132,133].…”

“…Importantly, the helper peptide was foreign and not expressed by the tumor, thus bypassing the issue that tumor-specific CD4 T cells are often tolerant [106,132,133]. These tumor-unrelated CD4 helper T cells not only substantially boosted dual costimulation-elicited control of the aggressive melanoma but also migrated into the tumors where they provided help to support CD8 + TIL and thereby diminished the frequency of intratumoral Foxp3 + Tregs [130]. Given their lack of tumor specificity, this result raises the intriguing question of how these dual costimulated CD4 T cells are triggered within tumors to elaborate help.…”