Vaccination with an NY\ESO\1 peptide inducing newly primed low\avidity Tconv cells did not induce an antigen\specific Treg cell response and therefore undermined the suppressive activity of Treg cells on high\avidity NY\ESO1\specific T\cell precursors
December 31, 2021
Vaccination with an NY\ESO\1 peptide inducing newly primed low\avidity Tconv cells did not induce an antigen\specific Treg cell response and therefore undermined the suppressive activity of Treg cells on high\avidity NY\ESO1\specific T\cell precursors.110 The most successful and widely applied form of cancer immunotherapy makes use of blocking antibodies to co\inhibitory receptors CTLA\4 and/or PD\1. on tumour cells, causing senescence,66 or indirectly by enhancing CTL effector differentiation.67, 68 Production of IFN\can NU 1025 also induce local chemokine secretion and therefore enhance the entrance of CTLs to the effector site. IFN\by CD4+ T cells and resulted in dampening of the CTL response, suggesting a negative feedback to limit unwanted CD8+ T\cell cytotoxicity.70 Additionally, CD4+ T cells can attract and modulate the activity of multiple innate immune cell types.71, 72 For example, upon recognition of tumour\derived antigens on macrophages and eosinophils, CD4+ T cells induced their activation and production of nitric oxide and superoxide leading to tumour growth inhibition.73 Moreover, IL\2 production by CD4+ T cells has been shown to enhance IFN\(IFN\(TGF\were shown to inhibit tumour\specific T\cell infiltration and effector function NU 1025 and to promote an anti\inflammatory phenotype in macrophages.91, 92, 93 Intratumoral Treg cells were also shown to play a role in the loss of effector function by CD8+ T cells. Recently, Treg\cell\derived IL\35 was shown to promote effector T\cell exhaustion within the tumour microenvironment.94 Treg cells were also shown to induce down\regulation of effector molecules and up\regulation of inhibitory receptors on CD8+ T cells. This process was dependent on reduction of co\stimulatory potential of intratumoral DCs. Depletion of Treg cells led to rescue and expansion of exhausted tumour\specific CTLs.95 In a model of chronic virus infection, a similar effect was dependent Mouse monoclonal to EGFP Tag on the provision of CD4+ T\cell help and co\stimulatory signals to the exhausted CTLs, highlighting the complementary roles of Tconv and Treg cells in maintaining functional CTL responses. 96 Treg cells have also been suggested to contribute to tumour progression by inducing angiogenesis. Hypoxic tumours were shown to attract Treg cells in a CCL28\dependent manner, which resulted in increased production of vascular endothelial growth factor A.97 On the other hand, Treg cells were shown to promote generation of memory CD8+ T cells.98 Expression of CTLA\4 and production of IL\10 by Treg cells have been shown to play a role during the contraction and resolution NU 1025 phase to promote memory CD8+ T\cell formation through the suppression of pro\inflammatory cytokine production by DCs.99, 100 Implications for cancer immunotherapy The goal of cancer immunotherapy is to elicit an effective CTL response. This can be achieved by reactivating pre\existing tumour\specific CTLs and/or by priming of naive tumour\specific CD8+ T cells. In an ideal scenario, cancer immunotherapy initiates and supports a cancer immunity cycle wherein the cancer acts as its own vaccine.101 Cancer cell killing releases tumour antigens that are presented to naive T cells in secondary lymphoid organs. As DC\activating danger signals are generally lacking in this scenario, appropriate therapeutic intervention may enhance priming of new CTLs and in turn increase the range of antigens that is recognized. The quality of tumour\specific CTL responses is modulated by both Tconv and Treg cells, as outlined above. It is therefore important to know how various cancer immunotherapy approaches affect both cell subsets. Current strategies involve therapeutic vaccination, treatment with immunomodulatory antibodies and adoptive cell transfer. Early studies in mice showed that vaccination with small peptides that directly bind to MHC class I molecules induced CD8+ T\cell tolerance, which could be overcome with agonistic anti\CD40 antibody and resulted in tumour\specific CTL responses.102 Follow\up studies demonstrated that vaccination with long peptides encompassing both MHC class I and class II epitopes induced optimal CTL\based anti\tumour immunity.103 Subsequently, inclusion of MHC class II epitopes in therapeutic vaccines has been shown to improve CTL responses and survival of patients with melanoma or vulvar neoplasia.104, 105, 106 Vaccination with mutant MHC class II epitopes was shown to drive the therapeutic response to established mouse tumours by inducing CD4+ T\cell responses. Observed effective anti\tumour CTL activity was linked in part to the decrease in intratumoral Treg cells following the vaccination.107 Recent studies in melanoma patients demonstrated that vaccination with a synthetic long\peptide or neo\antigen bearing RNA\transfected DCs resulted in potent CD4+ T\cell responses and durable tumour control.12, 13 Depletion of Treg cells might further improve the responses to vaccination. Application of recombinant IL\2Cdiphtheria toxin conjugate, resulting in Treg cell depletion, has been shown to NU 1025 enhance CTL responses following vaccination with RNA\transfected DCs.108, 109 Modulation of Treg cell activity can be also achieved by rational vaccine design. Vaccination with an NY\ESO\1 peptide inducing newly primed low\avidity Tconv cells did not induce an antigen\specific Treg cell response and therefore undermined the suppressive activity of Treg cells on high\avidity NY\ESO1\specific T\cell precursors.110 The most successful and widely applied form of cancer immunotherapy makes use of blocking antibodies to co\inhibitory receptors CTLA\4 and/or PD\1. Clinical benefit observed after the treatment with.