Cytokines and metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy

Abstract

Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors. For instance, dual costimulation immunotherapy with CD134 (OX40) plus CD137 (4-1BB) agonists appears to mediate tumor control in part by engaging cytokine networks that enable infiltrating CTL to compete for limiting supplies of glucose. Future efforts combining modalities that endow CTL with complimentary metabolic advantages should improve therapeutic efficacies.

OX40 and OX40L protein expression of tumor infiltrating lymphocytes in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers

“…Moreover, as a pivotal biomarker expressed in immune system, OX40 also serves as an important marker in associate with MEK, Dectin-1, RORγt+ CD8+ T Cells and other immune modulator in the anti-cancer immunology setting (76)(77)(78)(79)(80)(81)(82). To our knowledge, the activation of RAS/ MAPK pathway plays an important role in tumor growth and escape, and it is a common phenomenon in clinical cancer settings.…”

Costimulation Induces CD4 T Cell Antitumor Immunity via an Innate-like Mechanism

“…We also reasoned that this system would be ideal for developing strategies to overcome peripheral CD4 T cell tolerance induced by persistent antigen that could be critical for the development of therapeutics to boost immunity while preventing the suppression of T cell function as is typically important during cancer and infection. T cell costimulation through CD134 and CD137 induces robust CD8 and CD4 T cell immunity and is a powerful immunotherapeutic approach in cancer (Adler et al, 2017). To test whether dual costimulation (anti-CD134 agonist mAb combined with anti-CD137 agonist mAb) is able to prevent persistent antigen-induced CD4 T cell tolerance, specific TEα T cells were transferred (2.5 × 10 4 ) into the CD11c-Eα-IA b High or Low transgenic mice on day 0, and their response in the presence or absence of day 1 dual costimulation was tracked by flow cytometry.…”

Closely related reovirus lab strains induce opposite expression of RIG-I/IFN-dependent versus -independent host genes, via mechanisms of slow replication versus polymorphisms in dsRNA binding σ3 respectively

“…Reovirus-mediated oncolysis is a combination of both direct virus-induced cytolysis [ 49 – 53 ] and anti-tumor immune stimulation [ 54 – 59 ]. Given that cytokines, chemokines, and innate signalling molecules strongly influence anti-tumor immunity [ 60 – 64 ], we predict that they will impact anti-tumor immunity during reovirus oncolysis and contribute to the immunotherapeutic value of reovirus. Our data provokes a close investigation into the roles of RIG-I/IFN-dependent versus independent cytokines on reovirus-strain-specific anti-tumor activity.…”

“…Reovirus-mediated oncolysis is a combination of both direct virus-induced cytolysis [49][50][51][52][53] and anti-tumor immune stimulation [54][55][56][57][58][59]. Given that cytokines, chemokines, and innate signalling molecules strongly influence anti-tumor immunity [60][61][62][63][64], we predict that Model: T3D PL versus T3D TD induce opposite expression of RIG/IFN-dependent versus independent gene expression; attributed to slow replication versus polymorphisms in σ3 respectively. Previous studies described in text found that despite only 5 key polymorphisms, T3D strains had inherent differences in replication kinetics and in vivo oncolytic activities; with T3D TD being less oncolytic and slower replicating than T3D PL .…”