Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy

Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B. T-cell adhesion molecules and, in particular, lymphocyte-function-associated antigen-1 and CD103 integrins, and their cognate ligands, respectively, intercellular adhesion molecule 1 and E-cadherin, on target cells, are involved in strengthening the interaction between CTL and tumor cells. Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied cancers. TCRβ-chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate human leukocyte antigen class I-restricted cytotoxic activity toward autologous tumor cells. Several of them recognize truly tumor-specific antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward tumor neoantigens is associated with patient response to immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based vaccines. These tumor-specific mutation-derived antigens open up new perspectives for development of effective second-generation therapeutic cancer vaccines

Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice

Early responses of Tregs and effector T cells (Teffs) to their first encounter with tumor cells have been poorly characterized. Here we have shown, in both implanted and in situ–induced mouse tumor models, that the appearance of tumor cells is immediately sensed by CD44hi memory Tregs that are specific for self antigens. The rapid response of these Tregs preceded and prevented activation of naive antitumor Teffs. The relative speed of the Treg versus the Teff response within the first 2–4 days determined the outcome of the antitumor immune response: tolerance or rejection. If antitumor memory Teffs were present at the time of tumor emergence, both Tregs and Teffs were recruited and activated with memory kinetics; however, the Tregs were unable to control the Teffs, which eradicated the tumor cells. This balance between effector and regulatory responses did not depend on the number of Tregs and Teffs, but rather on their memory status. Thus, in the natural setting, dominant tolerogenic immunosurveillance by self-specific memory Tregs protects tumors, just as it protects normal tissues. More generally, our results reveal that the timing of Treg and Teff engagement, determined by their memory status, is an important mode of regulation of immune responses